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New Zealand Regulatory Guidelines for Medicines

Volume 1:
Guidance notes for applicants for consent to distribute new and changed medicines and related products

Fifth Edition
October 2001
Combining and updating previous editions of Volumes 1 and 2

NEW ZEA AN! REG" A#$R% G"&!E &NE' F$R ME!&(&NE'


V$ "ME 1
Guidance notes for a))licants for consent to distri*ute new and changed medicines and related )roducts

Fifth Edition
$cto*er +,,1
-(om*ining and u)dating )re.ious Volumes 1 and +/

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

Foreword
This document is the fifth edition of the Guidance Notes for Applicants for Consent to Distribute New and Changed Medicines and Related Products. It combines and replaces the fourth March !"""# edition of $olume ! and the second March !"""# edition of $olume %& Guidance Notes for Bioe ui!alence "esting. This new combined edition includes a number of changes in both content and format. 'ome te(t has been re)ised to reflect changes in polic* or processes. 'ome new sections and subsections ha)e been added+ some others ha)e been rearranged or deleted+ and the )arious forms pre)iousl* included in the main te(t ha)e been mo)ed to appendices at the end of the document. A more detailed list of changes is pro)ided below. These Guidelines are designed to assist sponsors in the preparation and submission of applications for consent to distribute new or changed medicines and related products in New ,ealand in accordance with the legislation. The* will be re)ised as needed and published on Medsafe-s web site http&..www.medsafe.go)t.n/#. Copies of the indi)idual forms gi)en in this )olume are also pro)ided as separate documents on the web site. Clare $an der 0em Manager Medsafe

!isclaimer While every care has been taken in the preparation of the information contained in these guidelines !edsafe is not responsible for the results of any act or omission done or omitted in reliance in whole or in part on the basis of that information nor for any error in or omission from the guidelines" #he information in the guidelines is of a general nature and should be used as a guide only to the provisions in the !edicines $ct 1%&1 !edicines 'egulations 1%&( !isuse of )rugs $ct 1%*+ !isuse of )rugs 'egulations 1%** subse,uent amendments and other relevant legislation"

Published with the permission of the Director-General of Health I'1N 234563%7%!432 Internet publication# I'1N 234563%7%!!37 1oo8#

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

'ignificant (hanges in this Edition


!. Volume 2 has been amalgamated with Volume ! to become 'ections !9 and !7. %. The fees schedule has been mo)ed to an appendi( at the end of the document. :. 'e)eral of the forms and chec8lists ha)e been re)ised and all ha)e been mo)ed out of the main te(t and into appendices at the end of the document. 4. The re;uirements of the <a/ardous 'ubstances and New =rganisms legislation and the >n)ironmental Ris8 Management Authorit* >RMA# ha)e been updated and e(panded 'ection %.!!.%#. 9. The re;uirements for recording and reporting the suppl* of unappro)ed medicines ha)e been updated section %.!:#. 7. A section dealing with Medical Ad)ertisements has been added 'ection %.!4#. 5. Processing times for applications and notifications ha)e been clarified 'ection 9.5#. 6. ?eb site addresses for o)erseas guidelines ha)e been updated 'ection 7."#. ". A new section detailing re;uirements for proprietar* names of therapeutic products has been added 'ection 7.!2#. !2. The re;uirements for Certificates of 'uitabilit* ha)e been updated and e(panded 'ection 5.%#. !!. The IC< Common Technical Document has been added as a preferred format for dossiers 'ection 6.!#. !%. The list of indi)idual German GMP inspectorates has been added 'ection !!.9#. !:. 0abelling re;uirements for transdermal patches ha)e been added 'ection !%.6#. !4. 0abelling re;uirements for =TC h*drocortisone topical products ha)e been added 'ection !%.!2."#. !9. A recommendation that the labelling for topical medicines should include a list of all of the ingredients has been added 'ection !%.!2.!7#. !7. The re;uirements for Consumer Medicine Information ha)e been updated and clarified 'ection !%.!%#. !5. The re;uirements and procedures for data sheets ha)e been updated 'ection !:#. !6. The policies and processes for compiling and maintaining the 0ist of Interchangeable Multi3 source Medicines ha)e been updated 'ection !4.4#. !". 'ome changes ha)e been made to re;uirements for batch si/es of test products used in bioe;ui)alence studies 'ection !9.9.7# and the re;uirement to re3anal*se !9@ of samples has been remo)ed 'ection !9.5.:#. %2. New NRPA and CRPN forms ha)e been created Appendices : and 5# and reference to related products has been remo)ed from the NMA and CMN forms Appendices %+ 9 and 7#. %!. A new chec8list for completeness of data for new multi3source prescription medicines has been created Appendi( 4#.

A**re.iations
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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

AAN AD>C ADR Ae AN=$A API ARTG AAC AAC AACt AACTC'' AACT' AACT'.AAC 1AN 1NB 1P CARM Ca) CBC Cma( CMI Cmin CMN Co' Cpd CPMP CPP CRPN Ct CTD DB DMB >C >M>A >P >RMA >A BDA B>$! GC GCRP GMP G'C <P0C

Australian Appro)ed Name Australian Drug >)aluation Committee Ad)erse drug reaction Cumulati)e urinar* reco)er* Anal*sis of )ariance Acti)e pharmaceutical ingredient Australian Register of Therapeutic Goods Area under the concentration )s. time cur)e AAC up to the last ;uantifiable concentration plus additional area infinit*+ calculated using 8el Area under the concentration )s. time cur)e AAC# measured to the last ;uantifiable concentration AAC measured o)er one dose inter)al T# at stead* state AAC o)er the dosing inter)al T# following a single dose of the Ratio of AAC o)er the dosing inter)al to the total AAC 1ritish Appro)ed Name 1ritish National Bormular* 1ritish Pharmacopoeia Centre for Ad)erse Reactions Monitoring A)erage concentration Chlorofluorocarbon Ma(imum obser)ed concentration Consumer Medicine Information Minimum obser)ed concentration Changed Medicine Notification Certificate of 'uitabilit* >uropean Pharmacopoeial Commission# Pre3dose concentration determined immediatel* pre3dose Committee for Proprietar* Medicinal Products C>uropeD Certificate of a Pharmaceutical Product Changed Related Product Notification The last ;uantifiable concentration Common Technical Document IC< format# Degree of fluctuation E Cma( 3 Cmin#. AACT.T# ( !22@ Drug Master Bile >uropean Communit*F or >uropean CommissionF or >nteric3coated >uropean Medicines >)aluation Agenc* C'ee Ph >urD >n)ironmental Ris8 Management Authorit* >uropean Anion Bood and Drug Administration CA'AD Borced e(pir* )olume in ! second Gas chromatograph* Good Clinical Research Practice Good Manufacturing Practice Generics 'ubcommittee of MAAC <igh pressure or performance# li;uid chromatograph* MR product e(trapolated to

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001 <RC <'N= IC< IMM IMMP INN 8el MAAC MARC MCA MCC M=< Mo< MoA MHC MR MRC MRT N1> NC> NB NMA NMA3< NMA3I NMA30 NR0 NRPA N, N,RGM N,RP =IA =TC Part I Part II Part III Part I$ Ph >ur P<ARMAC PMB PA r r% RP 'ACN 'C=TT 'MARTI 'PC tJ <ealth Research Council <a/ardous 'ubstances and New =rganisms Act International Conference on <armonisation Interchangeable Multi3source Medicine Intensi)e Medicines Monitoring Programme International Non3proprietar* Name Terminal elimination rate constant Medicines Assessment Ad)isor* Committee Medicines Ad)erse Reactions Committee Medicines Control Agenc* CAGDF or Medicines Control Ad)isor Medicines Classification Committee Medical =fficer of <ealth Ministr* of <ealth Memorandum of Anderstanding Minimum ;uantifiable concentration Modified release Medicines Re)iew Committee Mean residence time New 1iological >ntit* New Chemical >ntit* National Bormular* CA'AD New Medicine Application New higher3ris8 medicine application New intermediate3ris8 medicine application New lower3ris8 medicine application National Radiation 0aborator* New Related Product Application New ,ealand New ,ealand Regulator* Guidelines for Medicines New ,ealand Reference Product =fficial Information Act =)er The Counter Ci.e. non3 prescription productsD Administrati)e.summar* section of >uropean dossier Chemistr* I pharmaceutical section of >uropean dossier Pharmaco3to(icological section of >uropean dossier Clinical section of >uropean dossier >uropean Pharmacopoeia Pharmaceutical Management Agenc* 0td Plasma Master Bile Prescriber Apdate Correlation coefficient Coefficient of determination Related Product 'elf3assessable Change Notification 'tanding Committee on Therapeutic Trials Can <RC committeeD '*stem for the Management of Acti)ities+ Ris8s and Therapeutic Information CMedsafe databaseD 'ummar* of Product Characteristics >limination half3life

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001 TGA Tma( TPDR T'> A'AN A'NB A'P $'C ?<= Therapeutic Goods Administration CAustraliaD =bser)ed time at which Cma( occurred Therapeutic Product Database Report Cfrom 'MARTID Transmissible spongiform encephalopath* Anited 'tates Appro)ed Name Csee NBD Anited 'tates Pharmacopoeia $accines 'ubcommittee Cof MAACD ?orld <ealth =rganisation

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

(ontents
PAG> Section 1: Introduction.........................................................................................................................1 !.! Introducing Medsafe...................................................................................................................! !.!.! 'tatutor* responsibilities and accountabilities..........................................................................! !.!.% Regulator* framewor8..............................................................................................................! !.!.: Internal structure of Medsafe...................................................................................................% !.% Contacting Medsafe....................................................................................................................: !.: Medsafe-s ?eb 'ite....................................................................................................................9 !.4 =btaining Copies of New ,ealand 0egislation............................................................................7 Section 2: Therapeutic Products Controlled under New Zealand Legislation..................................7 %.! Medicines....................................................................................................................................5 %.% Related Products.........................................................................................................................6 %.: <erbal Remedies.........................................................................................................................6 %.4 <omeopathic Remedies...............................................................................................................6 %.9 Medical De)ices.........................................................................................................................." 2#$#1 %linical trials in!ol!ing medical de!ices##############################################################################& %.7 Cosmetics with a Therapeutic Purpose......................................................................................!2 %.5 Radiopharmaceuticals...............................................................................................................!2 %.6 Dietar* 'upplements.................................................................................................................!! %." Categorisation b* 'ubstance or Product T*pe...........................................................................!! %.!2 Therapeutic Purpose and Claims.............................................................................................!! %.!! Re;uirements to Compl* with =ther 0egislation and 'tandards..............................................!: 2#11#1 %onsumer legislation########################################################################################################1' 2#11#2 (a)ardous *u+stances and New ,rganisms legislation####################################################1' 2#11#' *tandards and -harmaco-oeia##########################################################################################1. %.!% Consent not to be used for Promotional Purposes ...................................................................!9 %.!: 'uppl*ing Anappro)ed Medicines...........................................................................................!9 %.!4 Medical Ad)ertisements .........................................................................................................!9 Section 3: pplication T!pes.............................................................................................................17 :.! ?hen is a Medicine a KNew MedicineLM...................................................................................!5 '#1#1 /!idence that a medicine has +een generally a!aila+le######################################################10 '#1#2 1re!iously a--ro!ed medicine that has not +een generally a!aila+le#################################12 '#1#' %om+ination -ac3s of currently a--ro!ed medicines##########################################################12 :.% ?hat is a New Acti)e 'ubstance M............................................................................................!6 :.: New Medicine Applications......................................................................................................!6 '#'#1 New higher4ris3 medicine a--lications###############################################################################12 '#'#2 New intermediate4ris3 medicine a--lications######################################################################1& '#'#' New lower4ris3 medicine a--lications#################################################################################1& :.4 Referrals under 'ection %4 9# of the Medicines Act !"6!.........................................................%2 :.9 Changed Medicine Notifications and Changed Related Product Notifications...........................%2 '#$#1 Material changes to medicines and related -roducts##########################################################20 Section ": #ees 22 4.! >)aluation Bees.........................................................................................................................%% .#1#1 New medicine or related -roduct a--lications####################################################################22 .#1#2 %hanged medicine5related -roduct notifications#################################################################22 .#1#. *elf4assessa+le change notifications###################################################################################2' 4.% Administration..........................................................................................................................%: 4.: Bee ?ai)ers..............................................................................................................................%4

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

Section $: d%inistrati&e Procedures...............................................................................................2$ 9.! >)aluation Processes for Applications and Notifications ..........................................................%9 $#1#1 New higher4ris3 medicine a--lications###############################################################################2$ $#1#2 New intermediate4 and lower4ris3 medicine and related -roduct a--lications###################26 $#1#' %hanged medicine notifications and changed related -roduct notifications#######################26 9.% Priorit* Assessment of New Medicine Applications..................................................................%7 $#2#1 %riteria for -riority assessment##########################################################################################20 $#2#2 1rocessing of -riority assessment a--lications###################################################################20 9.: Phases of the >)aluation Process..............................................................................................%6 $#'#1 New higher4ris3 medicine a--lications###############################################################################22 $#'#2 New intermediate4 and lower4ris3 medicine and related -roduct a--lications###################'1 $#'#' %hanged medicine or related -roduct notifications############################################################'2 9.4 Re;uests for Burther Information..............................................................................................:% 9.9 =utcomes of the >)aluation Process ........................................................................................:: $#$#1 Full consent#########################################################################################################################'' $#$#2 1ro!isional consent#############################################################################################################'' $#$#' 7ecline '. $#$#. 8ithdrawal##########################################################################################################################'. $#$#$ Re!ocation of consent or withdrawal from the mar3et########################################################'. 9.7 Database Report........................................................................................................................:9 9.5 Processing Times for Applications and Notifications................................................................:9 9.6 Protection of Confidential 'upporting Information....................................................................:5 $#2#1 1eriod of -rotection############################################################################################################'0 $#2#2 7isclosure of data###############################################################################################################'0 $#2#' Relationshi- with the ,fficial 9nformation :ct 1&22###########################################################'2 '#2#. /ffect on the e!aluation -rocess##########################################################################################'2 9." Certificate of Pharmaceutical Product.......................................................................................:6 9.!2 'hort 'uppl* and Discontinued Medicines..............................................................................:" Section ': (eneral )e*uire%ents +or pplications and Noti+ications..............................................", 7.! >ligibilit*..................................................................................................................................42 7.% 0anguage..................................................................................................................................4! 7.: Bormat 4! 7.4 Indi)idual Patient Data..............................................................................................................4% 7.9 Co)ering 0etter.........................................................................................................................4% 7.7 'ubmitting an Application or Notification.................................................................................4% 7.5 Apdating the Data Pac8age.......................................................................................................4: 7.6 'ponsors- Responsibilit* to Retain Copies of All Documents...................................................44 7." Technical Guidelines to be Bollowed.........................................................................................44 6#&#1 9%( guidelines####################################################################################################################.6 6#&#2 %1M1 guidelines#################################################################################################################.6 6#&#' F7: guidelines####################################################################################################################.0 7.!2 Proprietar* Names..................................................................................................................45 7.!! Description of Dosage Borm...................................................................................................46 7.!% Routes of Administration .......................................................................................................92 7.!: 'helf 0ife and 'torage Conditions...........................................................................................92 Section 7: Ingredients in -edicines and )elated Products.............................................................$1 5.! Drug Master Biles.....................................................................................................................9! 0#1#1 8hen is a 7MF not re uired;#############################################################################################$2 0#1#2 Format for a 7MF##############################################################################################################$2 5.% Certificate of 'uitabilit*............................................................................................................9: 5.: Ingredients of <uman or Animal =rigin....................................................................................9: 5.4 Colouring Agents......................................................................................................................94 Section .: New -edicine pplications .............................................................................................$$

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

6.! Bormats for New Medicine Applications...................................................................................99 2#1#1 Format for a new inno!ati!e medicine a--lication#############################################################$$ 2#1#2 Format for an a+ridged new medicine a--lication dossier#################################################$6 2#1#' 9%( and /< formats for a+ridged dossiers########################################################################$2 6.% Data Re;uirements for New Medicine Applications..................................................................72 6.: 'tandard Re;uirements for New Multi3source Generic# Prescription Medicines .....................7! Section /: Changed -edicine Noti+ications......................................................................................'7 ".! Bormat for Changed Medicine and Related Product Notifications.............................................75 ".% Data Re;uirements for Changed Medicine or Related Product Notifications.............................76 ".: 'elf3assessable Changes............................................................................................................5! ".4 Changes Not Re;uiring a CMN or CRPN.................................................................................5% &#.#1 %hanges in 1harmaco-oeial *-ecifications########################################################################02 &#.#2 %hanges in names of manufacturers or -ac3ers#################################################################02 &#.#' <-dates to 7rug Master Files#############################################################################################02 &#.#. <-dates to 1lasma Master Files#########################################################################################02 Section 1,: New and Changed )elated Products..............................................................................73 !2.! Data Re;uirements for New Related Product Applications.....................................................5: !2.% Data Re;uirements for Changed Related Product Notifications..............................................54 Section 11: (ood -anu+acturing Practice 0ocu%entation .............................................................7$ !!.! ?hen is GMP Documentation Re;uiredM................................................................................59 !!.% Recognised Documentation ....................................................................................................57 !!.: Classes of Medicine................................................................................................................55 !!.4 'ites which Manufacture 1ul8 Acti)e Pharmaceutical Ingredients .........................................55 !!.9 Recognised Authorities............................................................................................................56 Section 12: La1elling and Patient In+or%ation.................................................................................2 !%.! 0abelling of Medicines and Related Products..........................................................................6% !%.% 'ubmitting New and Changed Medicine 0abels......................................................................6% !%.: 0abelling Chec8lists and Declarations.....................................................................................6: !%.4 0abelling >(emptions..............................................................................................................64 !%.9 =)erlabelling or =)erstic8ing 0abels......................................................................................69 !%.7 Ph*sician-s 'ample Pac8s.......................................................................................................69 !%.5 'mall Containers.....................................................................................................................67 12#0#1 ,"% medicines##################################################################################################################26 12#0#2 *mall !olume medicines and related -roducts##################################################################26 !%.6 Transdermal Patches in Pouches or 'achets............................................................................67 !%." 'afet* Containers....................................................................................................................65 12#&#1 7efinition and use of safety containers############################################################################20 12#&#2 =a+elling of safety containers###########################################################################################20 !%.!2 'pecific Pac8aging and 0abelling Re;uirements for Certain Medicines................................66 12#10#1 :nti4an>iety or anti4insomnia medicines ########################################################################22 12#10#2 :ntihistamines#################################################################################################################2& 12#10#' Blood -roducts###############################################################################################################2& 12#10#. %ontact lens solutions#####################################################################################################2& 12#10#$ %ontrolled 7rugs############################################################################################################&0 12#10#6 %orticosteroids as a ueous solutions for nasal inhalation#############################################&0 12#10#0 Fluoride ta+lets###############################################################################################################&1 12#10#2 (e>achloro-hane############################################################################################################&1 12#10#& (ydrocortisone to-ical medicines###################################################################################&1 12#10#10 (24:ntagonists#############################################################################################################&2 12#10#11 9+u-rofen li uid#############################################################################################################&2 12#10#11 9odine############################################################################################################################&' 12#10#12 1aracetamol##################################################################################################################&' 12#10#1' 1holcodine#####################################################################################################################&.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

12#10#1. 1regnancy test 3its########################################################################################################&. 12#10#1$ *odium -hos-hate in oral +owel -re-arations##############################################################&$ 12#10#16 "o-ical medicines #########################################################################################################&$ 12#10#10 "o-ical medicines li3ely to +e used in the genital area#################################################&$ !%.!! Product Information 0eaflets................................................................................................."9 !%.!% Consumer Medicine Information..........................................................................................."7 Section 13: 0ata Sheets....................................................................................................................../7 !:.! Introduction............................................................................................................................."5 1'#2 1re-aring a 7ata *heet for :--ro!al##################################################################################&2 1'#2#1 Format &2 1'#2#2 %ontent##############################################################################################################################&2 1'#2#' 1re-aring a new data sheet for which there is an acce-ta+le source document###############&& 1'#2#. 1re-aring a data sheet for which there is no acce-ta+le source document#####################100 !:.: 'ubmitting Data 'heets for Appro)al and Publication..........................................................!29 1'#'#1 NM: for a new chemical or +iological entity medicine or a new !accine#######################106 1'#'#2 NM: for a new multi4source medicine############################################################################106 1'#'#' New dose form of an a--ro!ed medicine#########################################################################102 1'#'#. %MN for a new indication and5or new dosage instructions############################################102 1'#'#$ New or u-dated safety data#############################################################################################10& 1'#'#6 Miscellaneous changes to data sheets#############################################################################110 !:.4 <elpful <ints for Preparing Data 'heets for Publication.......................................................!!2 !:.9 Changes to Published Data 'heets ........................................................................................!!% !:.7 Additional 'afet* Information Re;uired in New ,ealand Data 'heets...................................!!: 1'#6#1 9ndi!idual medicines#######################################################################################################11' 1'#6#2 "hera-eutic Grou-s########################################################################################################11& Section 1": 2ioe*ui&alence and Interchangea1ilit!.........................................................................123 !4.! Introduction...........................................................................................................................!%: !4.% Choice of Reference Product ................................................................................................!%4 !4.: 1ioa)ailabilit* Data Re;uirements........................................................................................!%4 1.#'#1 1roduct ty-es that re uire com-arati!e +ioa!aila+ility data##########################################12. 1.#'#2 ?ustifying not su+mitting com-arati!e +ioa!aila+ility data############################################12$ 1.#'#' Medicines not re uiring com-arati!e +ioa!aila+ility data#############################################126 1.#'#. %hanges not re uiring further +ioe ui!alence testing####################################################120 !4.4 Interchangeabilit* of Multi3source Medicines........................................................................!%" 1.#.#1 *tyle and content of the 9nterchangea+le Multi4source Medicine =ist#############################12& 1.#.#2 New Zealand reference -roduct #####################################################################################1'2 1.#.#' Maintenance of the 9nterchangea+le Multi4source Medicine =ist###################################1'2 Section 1$: 2ioe*ui&alence Testing o+ 3ral -edicines..................................................................133 !9.! Introduction...........................................................................................................................!:: !9.% Important =)erseas 1ioe;ui)alence Guidelines.....................................................................!:: !9.: Definitions.............................................................................................................................!:4 !9.4 $ariables in a Comparati)e 1ioa)ailabilit* 'tud*.................................................................!:9 1$#.#1 />tent of a+sor-tion########################################################################################################1'$ 1$#.#2 Rate of a+sor-tion###########################################################################################################1'$ 1$#.#' 1harmacodynamic res-onses##########################################################################################1'6 1$#.#. %om-arati!e in !itro dissolution rate#############################################################################1'0 !9.9 Designing a Comparati)e 1ioa)ailabilit* 'tud*....................................................................!:5 1$#$#1 *ingle dose !ersus steady4state studies###########################################################################1'0 1$#$#2 1arameters #####################################################################################################################1'2 1$#$#' %hoice of su+@ects###########################################################################################################1'2 1$#$#. *tandardisation of e>-erimental conditions####################################################################1'& 1$#$#$ Num+er of su+@ects##########################################################################################################1'& 1$#$#6 Formulation and uality control data re uirements#######################################################1'& 1$#$#0 Num+er and timing of sam-les########################################################################################1.0

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

1$#$#2 Fasting and non4fasting studies######################################################################################1.1 1$#$#& Medicine administration#################################################################################################1.1 !9.7 Modified3release Products.....................................................................................................!4! 1$#6#1 %haracteristics################################################################################################################1.2 1$#6#2 1arameters######################################################################################################################1.' 1$#6#' *tudy design####################################################################################################################1.' 1$#6#. Re uirements for modified release formulations unli3ely to accumulate########################1.. 1$#6#$ Re uirements for modified release formulations li3ely to accumulate############################1.. !9.5 Anal*tical Methods...............................................................................................................!49 1$#0#1 %hromatogra-hic assay !alidation#################################################################################1.$ 1$#0#2 Radioimmunoassays########################################################################################################1.6 1$#0#' :ssay of study sam-les####################################################################################################1.6 !9.6 Reporting Data......................................................................................................................!45 !9." Presentation of 'ummarised Data..........................................................................................!46 !9.!2 'tatistical Anal*sis..............................................................................................................!4" 1$#10#1 Num+er of su+@ects########################################################################################################1.& 1$#10#2 :nalysis of !ariance A:N,V:B######################################################################################1.& 1$#10#' %onfidence inter!als######################################################################################################1$0 1$#10#. 1ower of :N,V:###########################################################################################################1$0 !9.!! Data Re;uirements..............................................................................................................!9! Section 1': 4*ui&alence Testing o+ Inhaled -edicines...................................................................1$3 !7.! Introduction...........................................................................................................................!9: !7.% Ph*sical e;ui)alence..............................................................................................................!94 16#2#1 Measuring -article si)e distri+ution################################################################################1$. 16#2#2 1article si)e ####################################################################################################################1$$ !7.: Clinical >;ui)alence..............................................................................................................!99 16#'#1 *tatistical analysis###########################################################################################################1$$ 16#'#2 4*ym-athomimetic medicines########################################################################################1$6 16#'#' :nticholinergic medicines###############################################################################################1$0 16#'#. Non4steroidal -ro-hylactic medicines#############################################################################1$0 16#'#$ Glucocorticoids###############################################################################################################1$2 !7.4 Powders for Inhalers.............................................................................................................!9" !7.9 Nasal Inhalation Products.....................................................................................................!9" !7.7 Changes to Currentl* Mar8eted Products..............................................................................!9" 16#6#1 Ru++er or -lastic com-onents#########################################################################################1$& 16#6#2 Re-lacement of chlorofluorocar+ons##############################################################################1$& 16#6#' %hanges to -owders for inhalation#################################################################################160 Section 17: Classi+ication and )eclassi+ication o+ -edicines..........................................................1'1 !5.! Medicines Classification Committee......................................................................................!7! !5.% Classification categories........................................................................................................!7! !5.: Birst 'chedule to the Medicines Regulations !"64.................................................................!7% !5.4 Classification of Controlled Drugs........................................................................................!7% !5.9 Classification of Medicines...................................................................................................!7% !5.7 Classification Criteria ..........................................................................................................!7: !5.5 Classification Process...........................................................................................................!74 !5.6 'ubmissions for Reclassification...........................................................................................!79 Section 1.: Clinical Trials o+ -edicines........................................................................................1'7 !6.! Introduction...........................................................................................................................!75 !6.% Application for Appro)al of a Clinical Trial ........................................................................!76 Section 1/: Phar%aco&igilance........................................................................................................1'/ !".! 'pontaneous Ad)erse Medicine Reaction Reporting 'cheme.................................................!7" !".% Intensi)e Medicines Monitoring Programme.........................................................................!52

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

!".: Responsibilit* of Companies to Report Ad)erse Medicine Reactions....................................!5! 1&#'#1 Re-orting ad!erse reactions to %:RM############################################################################101 1&#'#2 Re-orting su+stantial untoward effects of medicines######################################################101 1&#'#' Media interest in medicine safety issues##########################################################################101 !".4 Centre for Ad)erse Reactions Monitoring CARM#..............................................................!5% !".9 Medicines Ad)erse Reactions Committee..............................................................................!5% ppendi5 1: Schedule o+ #ees..........................................................................................................173 ppendi5 2: N- #or%..................................................................................................................17$ ppendi5 3: N)P #or%.................................................................................................................1.7 ppendi5 ": Chec6list +or New -ulti7source -edicine 0ata.........................................................1/2 ppendi5 $: C-N #or% ..............................................................................................................2," ppendi5 ': C-N #or% 2..............................................................................................................21/ ppendi5 7: C)PN #or% ................................................................................................................231 ppendi5 .: La1elling 0eclaration..................................................................................................2"1 ppendi5 /: La1elling Chec6list +or -edicines..............................................................................2"3 ppendi5 1,: La1elling Chec6list +or Contact Lens Solutions.......................................................2". ppendi5 11: La1elling Chec6list +or )elated Products................................................................2$1 ppendi5 12: 0ata Sheet 0eclaration.............................................................................................2$" ppendi5 13: Chec6list +or NZ #or%at 0ata Sheet........................................................................2$7 ppendi5 1": #or% +or )eporting Suppl! o+ 8nappro&ed -edicine............................................2'2 ppendi5 1$: #or% +or )eporting d&erse )eaction to -edicines9 :accines9 -edical 0e&ices and I--P......................................................................................................................2'" ppendi5 1': #or% +or )eporting d&erse )eaction to #ractionated 2lood Products................2''

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

'ection 1:

&ntroduction

101

&ntroducing Medsafe

Medsafe is the regulator* authorit* for therapeutic products in New ,ealand. The mission statement of Medsafe is 3

Healthy New Zealanders *y: regulating medicines and medical de.ices to ma1imise safety and *enefit

10101

'tatutory res)onsi*ilities and accounta*ilities

The regulator* responsibilit* of Medsafe is to administer the Medicines Act !"6! and parts of the Misuse of Drugs Act !"59+ and their accompan*ing Regulations. The obNecti)e of the medicines legislation is to manage the ris8 of a)oidable harm associated with the use of medicines. The legislation is designed to ensure that& medicines conform to acceptable standards of safet*+ ;ualit* and efficac* personnel+ premises and practices used to manufacture+ store and distribute medicines compl* with re;uirements to ensure the continued conformit* of the products to those standards until the* are deli)ered to the end3user information about the selection and safe use of medicines is pro)ided to consumers and prescribers of medicines. In carr*ing out its functions+ Medsafe is accountable to& the Minister of <ealth through delegations and the Purchase Agreement between the Ministr* of <ealth and the Minister of <ealth the Ministr* of <ealth for regulator* acti)ities and for polic* ad)ice or public good acti)ities funded b* the Crown the pharmaceutical industr* for those acti)ities which are funded b* fees collected from the industr*.

1010+

Regulatory framewor2
!

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

Medsafe-s mission is accomplished b* appl*ing a framewor8 that ensures benefits in the use of therapeutic products while managing the potential ris8s. >nsuring that the therapeutic products a)ailable in New ,ealand are those which can be e(pected to ha)e greater benefits than ris8s+ if used appropriatel*+ is achie)ed through a pre3mar8eting appro)al s*stem and post3mar8eting sur)eillance. The pre3mar8eting appro)al s*stem is outlined in this publication. New medicines and related products cannot be mar8eted in New ,ealand without the consent of the Minister of <ealth or delegated authorit*#. Changed medicines and related products cannot be mar8eted without the consent of the Director3General of <ealth or delegate#. Data that satisfactoril* establish the ;ualit*+ safet* and efficac* of the product+ for the purposes for which it is to be used+ must be submitted to Medsafe for e)aluation before consent can be granted. The appro)al s*stem is independent of the Go)ernment-s subsidisation of medicines managed b* P<ARMAC+ e(cept that P<ARMAC ma* re;uest fast3trac8ing of e)aluation of certain new medicine applications where significant cost sa)ings ma* result from a)ailabilit* of the medicines concerned on the New ,ealand mar8et. Post3mar8eting sur)eillance monitors the safet* of medicines and medical de)ices in use. Products shown to be unsafe are remo)ed from use+ and prescribers are ad)ised about new safet* information for other products. Post3mar8eting sur)eillance is achie)ed through& pharmaco)igilance 3 the spontaneous reporting of ad)erse effects of medicines and the Intensi)e Medicines Monitoring Programme+ and through monitoring the international literature and other international sources routine monitoring+ such as testing mar8eted medicines against product ;ualit* standards auditing and licensing of medicine manufacturers+ pharmacies etc.

10103

&nternal structure of Medsafe

Medsafe consists of three operational teams and operates out of four sites nation3wide+ with centralised administrati)e functions and product appro)al and standard setting based at the ?ellington office. The 4&aluation Tea% pro)ides ad)ice to the Minister and Director3General of <ealth on the ;ualit*+ safet* and efficac* of medicines and related products which are proposed for distribution in New ,ealand. The Co%pliance Tea% ensures that therapeutic products and persons in)ol)ed in their manufacture+ distribution and use compl* with legislati)e re;uirements. The 2usiness 0e&elop%ent and Support Tea% de)elops polic*+ strategic direction and business opportunities for Medsafe+ o)ersees medicine classification and pharmaco)igilance+ and pro)ides prescribers+ pharmacists and consumers with information about the safe use of medicines and medical de)ices.

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

10+

(ontacting Medsafe
-edsa+e P3 2o5 $,13 ;ellington -edsa+e Le&el 1. (rand Pli%%er Tower 27' (il%er Terrace ;ellington ,"< "/' 2,,, ,"< "/' 222/ http:==www.%edsa+e.go&t.n>

Medsafe ma* be contacted at the following addresses& Postal Address:

'treet.Courier Address&

Telephone& Ba(& Internet address&

Indi)idual staff members can be contacted b* e3mail using the following Internet address& +irst na%e?surna%e@%oh.go&t.n>. -edicine e&aluation en*uiries Administrati)e en;uiries should be directed to the ?or8flow Co3ordinator+ >)aluation Team at the abo)e address#. Complaints and feedbac8 should be directed to the >)aluation Team 0eader. Technical issues following receipt of a ;uer* letter# should be directed to the e)aluator. pplications and su1%issions New Medicine and Related Product Applications+ Changed Medicine and Related Product Notifications and O'ection %"- reports should be forwarded to the Manager+ Medsafe at the abo)e address#. Note: ?hen a large application dossier is deli)ered to Medsafe+ the courier should be ad)ised not to deli)er the bo(es to the reception des8 on the !6 th floor of Grand Plimmer Tower. The courier should contact reception to notif* their arri)al and arrange access to the loc8ed storage area on a lower floor of the building. Re;uests for a Certificate of Pharmaceutical Product should be forwarded to the 'upport =fficer+ >)aluation Team. 'ubmissions to reclassif* a medicine should be forwarded to the 'ecretar*+ Medicines Classification Committee+ Medsafe.

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

Clinical trial applications and ;ueries Borward ! cop* of the application to the Manager+ Medsafe and 4 copies to the Chairperson of the 'tanding Committee on Therapeutic Trials 'C=TT#& 1ostal :ddress& Assoc. Prof. R Robson P= 1o( %697 Christchurch %ourier :ddress& Assoc. Prof. R Robson c.3 The Pegasus Centre :! Tuam 'treet Christchurch Attention& The 'ecretar*#

Hueries about applications for clinical trials should be made to the 'upport =fficer+ >)aluation Team+ Medsafe. -edicine control and co%pliance en*uiries Medicine control issues e.g. licences to pac8+ wholesale+ haw8 medicines# should be directed to Medicine Control ad)isors at the local Medicine Control =ffices. Contact details are as follows& Northern Medicines %ontrol ,ffice A'1 1an8+ 0e)el ! 63!% 0in8 Dri)e ?airau Par8 P= 1o( !22 !77 Auc8land Telephone 2"# 44! :752 Ba( 2"# 44! :76" %entral Medicines %ontrol ,ffice !6th Bloor+ Grand Plimmer Tower %37 Gilmer Terrace P= 1o( 92!: ?ellington Telephone 24# 4"7 %4:5 Ba( 24# 4"7 %%%" *outhern Medicines %ontrol ,ffice 4 %hristchurch National Radiation 0aborator* !26 $ictoria 't P= 1o( %9 !55 Christchurch Telephone 2:# :77 5:"4 Ba( 2:# :77 !!97 *outhern Medicines %ontrol ,ffice 4 7unedin "th Bloor+ Pohn ?ic8liffe <ouse Princes 't P= 1o( :64 Dunedin Telephone 2:# 45" %97! Ba( 2:# 455 7::6

=ther compliance issues should be directed to the Compliance Team+ Medsafe+ at the ?ellington address gi)en abo)e. These ma* include& recalling of a medicine+ ad)ertising of medicines+ audits
of medicine manufacturers etc.

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

103

Medsafe4s We* 'ite

Medsafe-s web site http:==www.%edsa+e.go&t.n> includes the information listed below and sponsors and applicants are encouraged to )isit the site regularl* and ta8e note of an* new information or changes to re;uirements and guidelines published there. 1out -edsa+e
?ho we are ?hat we do $ision and )alues 0egislation sources# Contacting us contact addresses# Mail order for Medsafe publications# 0in8s to rele)ant New ,ealand and o)erseas health and pharmaceutical web sites# $acancies an* )acancies in Medsafe#

In+or%ation +or Consu%ers


<ow medicines are regulated 'afe use of medicines Consumer Medicine Information Information about medicines Information about complementar* healthcare products Pharmacist =nl* medicines Medical de)ices Reporting a side3effect Ma8ing a complaint 'upport groups

In+or%ation +or Aealth Pro+essionals


Prescriber Apdate articles Regulator* issues Clinical trials Recent changes to medicines Medicine Data 'heets Consumer Medicine Information Interchangeable Medicines Anappro)ed Medicines Classification of Medicines Medicine suppl* issues Medical de)ice issues Reporting an ad)erse reaction Reporting a defect Drug abuse issues

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

)egulator! In+or%ation
Guidelines and Codes Borms Bees Medicines Assessment Ad)isor* Committee Blu )accine formulation Data 'heets and CMI Consumer Medicine Information# 0icensed manufacturers Anappro)ed medicines In)estigations testing programmes carried out b* Medsafe and summarised results# Ga/ette Notices includes consents to distribute new or changed medicines and related products# Ad)ertising Consultants names and details of consultants who pro)ide independent regulator*+ clinical and other ser)ices to the pharmaceutical sector#

Aot Topics
Media releases Discussion papers =ther issues#

Site In+or%ation
Downloading 1est )iewed with Disclaimer Coming attractions

105

$*taining (o)ies of New Zealand egislation

Copies of the New ,ealand legislation referred to in these guidelines ma* be purchased from an* of the following& 1ennetts Go)ernment 1oo8shop :72 Hueen 'treet P= 1o( 99!: Auc8land Telephone 2"# :55 :4"7 Ba( 2"# :55 :4"5 1ennetts Go)ernment 1oo8shop 1owen <ouse Corner of 1owen 't and 0ambton Hua* P= 1o( 9::4 ?ellington Telephone 24# 4"" :4:: Ba( 24# 4"" ::59 1roo8er-s 0td P= 1o( 4: ?ellington Telephone 24# 4"" 6!56 Ba( 24# 4"" 6!5:

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

'ection +:

#hera)eutic 6roducts (ontrolled under New Zealand egislation

Section summary "he medicines legislation controls -roducts used in humans for a thera-eutic -ur-ose# 1roducts used for a thera-eutic -ur-ose can +e categorised as medicines, related -roducts, her+al remedies or medical de!ices# "hese terms are e>-lained in this section# : -roduct is considered to +e intended for a thera-eutic -ur-ose if a thera-eutic claim is stated or im-lied in the -roduct la+elling or -romotional material, or where the acti!e ingredientAsB clearly has a -harmacological action# "his section descri+es the sorts of statements considered to +e thera-eutic claims# Legislation to read in conjunction with this section Medicines :ct 1&21 *ection 2C 9nter-retation and meaning of Dmedical de!iceE *ection 'C Meaning of DmedicineE, Dnew medicineE, D-rescri-tion medicineE and Drestricted medicineE *ection .C Meaning of Dthera-eutic -ur-oseE *ection 22C />em-tions in res-ect of her+al remedies *ection &.C Meaning of Drelated -roductE 1art 9VC Medical ad!ertisements 7ietary *u--lement Regulations 1&2$ Regulation 2C 9nter-retation Regulation 11C "hera-eutic claims

+01

Medicines

The term KmedicineL is defined in section : of the Medicines Act !"6!. In practical terms+ a product is a medicine if it is administered to humans primaril* for a therapeutic purpose. Most+ but not all+ medicines ha)e a pharmacological effect. Therapeutic purpose is defined in section 4 of the Act+ and includes the treatment+ diagnosis and pre)ention of disease or the modification of a ph*siological function. It also includes cleaning+ soa8ing or lubricating contact lenses+ inducing anaesthesia+ or effecting contraception. 'permicidal condoms and intrauterine de)ices IADs# containing copper or a hormone are medicines whereas non3spermicidal condoms and other barrier3t*pe contracepti)es e.g. diaphragms# are de)ices. 9n !i!o diagnostic agents are medicines while in !itro diagnostic products are de)ices with the e(ception of pregnanc* test 8its which are medicines#. The onl* products that are regulated as medicines+ but are not actuall* administered to humans+ are pregnanc* test 8its. The consent of the Minister is re;uired before a new medicine can legall* be distributed in New ,ealand e(cept in the case of certain specified e(emptions+ as e(plained later in this document#. Medicines that are also Controlled 0rugs are controlled under the Medicines Act !"6! and associated Medicines Regulations and also the Misuse of Drugs Act !"59 and associated Misuse of Drugs Regulations. In accordance with section !2" 4# of the Medicines Act+ where a product is controlled under both sets of legislation+ the Misuse of Drugs legislation ta8es precedence in the e)ent of an* inconsistenc*.

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

The following are not medicines and the Minister-s consent is not re;uired for their distribution in New ,ealand& 'ubstances used in dental surger* for filling dental ca)ities these are medical de)ices# Non3medicated bandages and other surgical dressings these are medical de)ices#. CMedicated dressings where the medication has a curati)e function that is not limited to sterilising the dressing are medicines b* legislation.D Radioacti)e materials used for a therapeutic purpose. These are specificall* e(cluded from the Medicines legislation+ but are subNect to other controls. 'ee 'ection %.5 below.#

+0+

Related 6roducts

A related product is a product that is primaril* a food+ dentifrice or cosmetic+ but has a secondar* therapeutic use. This term is defined in section "4 of the Medicines Act. The consent of the Minister is re;uired before a new related product can legall* be distributed in New ,ealand. The legislation does not re;uire a related product to be manufactured in a factor* licensed to manufacture medicines+ but the manufacturer must compl* with an appropriate standard of GMP see section !!#. >(amples of related products include the following& Bluoride toothpastes containing not more than 2.!@ elemental fluorine Toothpastes containing more than 2.!@ elemental fluorine are classified as pharmac*3onl* medicines.# Note that fluoride mouthwashes intended to be swallowed as a supplement are medicines. Antidandruff shampoos In addition+ the following ha)e traditionall* been treated as elated products& Antiseptic throat lo/enges Bungicidal lo/enges are restricted medicines.# Antiseptics used for cleaning wounds+ cuts+ abrasions+ stings+ insect bites and superficial burns.

+03

7er*al Remedies

A herbal remed* is a special sub3categor* of medicine+ defined in section % of the Medicines Act. A herbal remed* is a medicine that does not contain a prescription+ restricted or pharmac*3onl* medicine+ and consists of a substance deri)ed from plant material that has been dried or crushed or deri)ed through an* other similar process#. It ma* also be an a;ueous or alcoholic e(tract of the dried or crushed plant material+ or a mi(ture of that material with another inert substance. Ministerial consent is not re;uired for the distribution of a herbal remed* which is sold or supplied without an* recommendation as to its use and the labelling complies with the re;uirements of section %6 of the Medicines Act+ whereas Ministerial consent is re;uired for the distribution of a herbal remed* which is sold with a recommendation for use for a therapeutic purpose.

+05

7omeo)athic Remedies

A homeopathic remed* which is prepared under the principle of homeopath* in which the acti)e ingredient to be administered is in a concentration not more than %2 parts per million+ and the remed* is labelled onl* with the name of the acti)e ingredient+ trade name if an*# and a statement that it is a homeopathic remed* does not normall* re;uire Ministerial consent before distribution. The product label or associated ad)ertising material must not contain therapeutic claims or indications for use. A homeopathic remed* which is labelled or ad)ertised with claims as to its therapeutic purpose is a medicine and subNect to the full control of the Medicines legislation.

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

'terile homeopathic preparations intended for inNection or for administration to the e*es are regarded as medicines and therefore subNect to the full control of the Medicines legislation

+08

Medical !e.ices

The term medical de)ice is defined in section % of the Medicines Act !"6!. A medical de)ice is an* de)ice+ instrument+ apparatus etc. used primaril* b* humans for a therapeutic purpose. This includes bandages and surgical dressings pro)ided the* are not medicated with a therapeutic agent if medicated+ the* are medicines#. Ander current legislation+ ministerial consent is not re;uired for the distribution of medical de)ices. <owe)er+ some medical de)ices are subNect to specific legal re;uirements& All condoms distributed in New ,ealand are re;uired b* law to compl* with either the International 'tandard I'= 42543!&!""7 ># Ru++er %ondoms or the New ,ealand 'tandard N,' 5!27&!""6 1olyurethane %ondoms as applicable. All intra3uterine contracepti)e de)ices are re;uired to compl* with the New ,ealand 'tandard N,' 5!2%&!"62 *-ecification for 9ntra4uterine %ontrace-ti!e 7e!ices . Note& New ,ealand legislation classifies a number of products as medicines while o)erseas these are classified as medical de)ices e.g. pregnanc* test 8its#. Registration of medical de)ices is e(pected to become a legal re;uirement in the future under proposed legislation. Medsafe is wor8ing closel* with the Australian TGA on harmonising New ,ealand and Australian controls on medical de)ices. Medsafe is currentl* de)eloping regulations which will re;uire a register of medical de)ices so that de)ice trac8ing in New ,ealand can be maintained until new legislation is de)eloped. Burther details can be obtained from Medsafe. New ,ealand and Australia ha)e a Noint reporting s*stem for ad)erse reactions to medical de)ices. A medical de)ice incident reporting form is on Medsafe-s web site. An* concerns with the safet* of a medical de)ice distributed in New ,ealand should be reported to Medsafe. An* alerts or recalls o)erseas should also be reported if the de)ice is distributed in New ,ealand.

+0801

(linical trials in.ol.ing medical de.ices

Medsafe is wor8ing towards aligning the re;uirements for conducting clinical trials on medical de)ices with the Australian Therapeutic Goods Administration. ?hen a trial is intended+ Medsafe should be informed of the name of the de)ice under trial and details of the trial+ the compan* co3ordinating the trial+ and the hospitals or clinics in)ol)ed in the trial. Progress reports should be submitted to Medsafe. A compan* wishing to conduct a clinical trial on a medical de)ice must& label the de)ice to show that it is to be used onl* in a clinical trial+ and source the de)ice from a factor* operating suitable good manufacturing practices+ and ensure that the clinical trial complies with the New Zealand Regulatory Guidelines for Medicines, Volume 'C 9nterim New Zealand Guide to Good %linical Research 1ractice+ and obtain appro)al from the appropriate institutional ethics committee s#+ and

"

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

ad)ise all patients who will recei)e the de)ice of the international status of the de)ice. The* must also be informed that the* are part of a clinical trial and must be informed of an* ris8s associated with the de)ice.

+09

(osmetics with a #hera)eutic 6ur)ose

'ection % of the Medicines Act !"6! defines a cosmetic. In general terms+ a cosmetic is a product used to cleanse+ protect or beautif* the hair or s8in. The following t*pes of products+ when sold without an* therapeutic claims and not containing an* substance listed in the Birst 'chedule of the Medicines Regulations !"64 and amendments# are considered to be cosmetics+ and the Minister-s consent for distribution is not re;uired for their distribution& Antiperspirants Deodorants Insect repellents Dusting powders 'unscreen and suntan preparations Cleansers for normal or blemished s8in Moisturisers for normal+ sunburnt or wind burnt s8in <air conditioners Astringents and s8in toners Agents to assist in the fading of spots+ pimples and blemishes Antiseptics for generalised+ all3o)er use+ on the bod* and not on bro8en s8in 'olutions which are bathed in to rela( the bod* Anti3wrin8le and anti3ageing products which ha)e a superficial cosmetic effect and not a ph*siological effect.

Cos%etics must not be ad)ertised as ma8ing basic underl*ing changes to the s8in such as cellular changes. Sunscreens are currentl* categorised as cosmetics and do not re;uire appro)al or Ministerial consent before mar8eting. Companies are encouraged to mar8et onl* sunscreens that compl* with the Australian.New ,ealand 'tandard A'.N,' %724&!""6 *unscreen 1roducts 4 /!aluation and %lassification. Companies mar8eting sunscreens should ha)e e)idence to support the 'PB and broad spectrum protection claimed. Buture legislation ma* control sunscreens as therapeutic products.

+0:

Radio)harmaceuticals

Radiopharmaceuticals are not controlled under the Medicines Act or Medicine Regulations administered b* Medsafe. Control of the import and use of radiopharmaceuticals in New ,ealand is the responsibilit* of the National Radiation 0aborator* NR0#. An*one intending to import radioacti)e materials into New ,ealand must ha)e the consent of the Director of the NR0. An* hospital+ clinic or medical practitioner intending to administer radiopharmaceuticals to a patient or patients for the purpose of diagnosis or treatment must be licensed to do so b* the NR0. Burther information ma* be obtained from&

!2

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

The General Manager National Radiation 0aborator* !26 $ictoria 'treet P= 1o( %9!55 Christchurch New ,ealand Telephone& 2:# :77 929" Ba(& 2:# :77 !!97

+0;

!ietary 'u))lements

Dietar* supplements are controlled under the Dietar* 'upplements Regulations !"69. Regulation % of these Regulations defines a dietar* supplement. In practical terms+ a dietar* supplement is an edible substance+ in a controlled dosage form+ which is intended to supplement the inta8e of substances normall* deri)ed from food. A product mar8eted as a dietar* supplement ma* not be promoted for a therapeutic purpose. Companies wishing to ma8e therapeutic claims for such products must appl* for consent to distribute the product as a medicine or related product.

+0<

(ategorisation *y 'u*stance or 6roduct #y)e

If a product is administered to humans and contains a substance that e(erts a therapeutic effect+ that product is considered to be a medicine+ irrespecti)e of whether therapeutic claims are made on the label or in ad)ertising material. Bor e(ample+ a product containing a hormone is a medicine+ regardless of the purpose for which it is being promoted. The Birst 'chedule of the Medicines Regulations !"64 contains a list of Prescription+ Restricted and Pharmac*3=nl* Medicines. It also contains some KclassL classifications e.g. anore(iants#. The Birst 'chedule is therefore a useful guide to determining whether or not a product is considered to be a medicine. <owe)er+ please note that listing of a particular medicine in the Birst 'chedule does not necessaril* mean that it is currentl* appro)ed for distribution in New ,ealand+ but rather+ that it would be classified as indicated if it was appro)ed for distribution.

+01,

#hera)eutic 6ur)ose and (laims

There ma* be se)eral indicators that a product has a therapeutic purpose. These ma* include& the trade name of the product con)e*ing an intended purpose use of the words remedy+ medicated or thera-eutic statements of historical therapeutic use+ or use b* ethnic groups for a therapeutic purpose directions for use+ such as *-read on affected area use of statements to the effect that the manufacturers are prohibited from ma8ing specific claims about the product.

A therapeutic claim can be direct+ implied+ or suggested. 'tatements that a product will.can.ma*.is intended to gi)e relief from a disease+ pain+ or s*mptoms associated with a disease are therapeutic claims. Nutritional statements+ or statements relating to the normal biochemical or ph*siological function of a substance+ are not considered to be therapeutic claims. The following is a guide to the sorts of claims made for products.

!!

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

Gastro=intestinal system A claim such as Beneficial for the digesti!e tract# Good for a+dominal cram-s is regarded as a therapeutic claim+ since it implies or indicates treatment for an ad)erse ph*siological condition. If Good for a+dominal cram-s were remo)ed+ the product would not be considered a therapeutic product. A claim such as *u--orts the healthy function of 3idneys, li!er and digesti!e tract is regarded as a broad statement relating to normal biochemical function+ hence the product would not be considered a therapeutic product. A claim such as Beneficial for digestion and intestinal com-laints# <se for cholesterol control is regarded as a therapeutic claim+ both because the product is implied.intended for the alle)iation or treatment of intestinal complaints+ and because it is intended to reduce cholesterol. A claim such as For the formation of a num+er of im-ortant +iological su+stances re uired for many !ital cellular functions would be regarded as a broad statement relating to nutritional needs+ and not a therapeutic claim. "rinary system A claim such as (el-s maintain the healthy function of urinary organs# (as anti4inflammatory -ro-erties is considered to be a therapeutic claim since it implies that maintenance is b* means of the anti3inflammator* properties of the product. A claim such as Beneficial for the genito4urinary system# <se for fluid retention is regarded as a therapeutic claim since it is implied the product treats fluid retention. If the sentence <se for fluid retention is remo)ed+ the claim would fall into the categor* of a statement relating to normal biochemical or ph*siological function. (ardio.ascular system A claim such as :nti4throm+otic, cholesterol4su--ressi!e for an edible product is regarded as a therapeutic claim because the product would be mar8eted for these purposes+ rather than for its nutritional purpose. Res)iratory system A claim such as Beneficial and soothing for the res-iratory system# :lle!iates mucous congestion is regarded as a therapeutic claim+ since the product is implied or intended to relie)e a particular s*mptom of an ad)erse ph*siological condition. (entral ner.ous system A claim such as "em-orary relief of slee-lessness and e>cita+ility is considered to be a therapeutic claim since the product is principall* intended to act as a sedati)e+ and would not ha)e a nutritional purpose. Musculos2eletal system A claim such as Beneficial for the tem-orary relief of -ain due to arthritis, rheumatism, menstruation and muscular -ain is regarded as a therapeutic claim. Generall*+ all products intended to be analgesics+ or acting b* means of an analgesic effect+ are therapeutic products. $*stetrics and gynaecology A claim such as :--ly for na--y rash or :--ly to crac3ed ni--les is regarded as a therapeutic claim since the product would purport to relie)e these ph*siological conditions. Eye> ear> nose> mouth and throat A claim such as Remo!es -ro+lem4causing +acteria which cause +ad +reath or Remo!es -la ue would not normall* be considered to be a therapeutic claim unless the product is also intended to treat conditions such as gingi)itis. A claim such as Relie!es sore throats or *oothes sore throats for a lo/enge is regarded as a therapeutic claim because an anaesthetic action is in)ol)ed.

!%

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

'2in A claim such as 7isinfection of hands and s3in would not be regarded as a therapeutic claim. Con)ersel*+ a claim such as For the -re!ention of infection in wounds, cuts and a+rasions is a therapeutic claim because the product would be applied to bro8en s8in. A claim such as Fee-s s3in smooth and resilient would not be regarded as a therapeutic claim. A claim such as Remo!es oil, ma3e4u- and dirt without o!er4drying# Medicated to 3ill -ro+lem4 causing +acteria would not generall* be regarded as a therapeutic claim in spite of the use of the word Omedicated-+ unless the product is intended to be used or has an implied use on a specific s8in condition. A claim such as 1romoting hair growth or 9ncreasing nutrient su--lies for follicles would be regarded as a therapeutic claim+ since baldness and its associated ph*siological condition is listed in the Birst 'chedule to the Medicines Act !"6!.

+011

Re?uirements to (om)ly with $ther egislation and 'tandards


(onsumer legislation

+01101

Medicines+ related products and medical de)ices are regulated b* the Ministr* of <ealth in accordance with the Medicines and Misuse of Drugs legislation. 'ponsors should also be aware that+ as these products are articles of commerce+ the* also need to compl* with an* other rele)ant consumer legislation e.g. the Bair Trading Act !"67# administered b* the Ministr* of >conomic De)elopment.

+0110+

7a@ardous 'u*stances and New $rganisms legislation

Certain medicines must compl*+ not onl* with the Medicines legislation+ but also with the re;uirements of the <a/ardous 'ubstances and New =rganisms Act !""7 <'N=#+ its amendments and its associated regulations as administered b* the >n)ironmental Ris8 Management Authorit* New ,ealand >RMA#. Most human medicines in finished dose form are e(empt from the <'N= legislation e)en when the* cross the <'N= thresholds for ha/ardous properties. <owe)er+ the following t*pes of new human medicines are not e>em-t and must compl* with the <'N= legislation& 'ubstances that are gases e.g. medical gases# contained in pressure containers of more than !22 mls and at pressures of more than !52 8Pa+ up until the time the* are administered to one or more human beings for a therapeutic purpose. New medicines e.g. )accines or gene therap* products# that contain li)e or attenuated )iruses or bacteria and are Knew organismsL as defined in section % A# of the <'N= Act !""7. To be a new organism it must be Ka species of an* organism which was not present in New ,ealand on the date of commencement of this ActL i.e. %" Pul* !""6#. Bor the purposes of the <'N= legislation+ genetic modification of a pre)iousl* present species of a micro3organism produces a new organism. Medicines co)ered b* the e(emption appl*ing to human medicines are not e(empt from the <'N= legislation when used as )eterinar* medicines. 'ubstances used in the manufacture of medicines in New ,ealand b* licensed medicine manufacturers are not e(empt and importers and manufacturers must compl* with the <'N= legislation. The web site http:===www.hsno.go&t.n> is dedicated to the <'N= legislation and its application.

!:

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

The web site http:==www.er%an>.go&t.n> includes information on >RMA procedures together with a searchable register of applications and appro)als under the <'N= Act. ?here a sponsor wishes to distribute a new medicine that is a medical gas or new organism as defined abo)e+ the sponsor must appl* separatel* to both Medsafe and >RMA for consent using their respecti)e application forms and procedures. Details of the date and status of the application to >RMA must be pro)ided on the New Medicine Application form see Appendi( % of these Guidelines#. The medicine concerned ma* not be distributed in New ,ealand until consent from both agencies has been granted. In the e)ent of such an application to Medsafe and >RMA+ the two agencies will wor8 together subNect to an* confidentialit* limitations imposed b* the applicant#+ sharing rele)ant information and e)aluation reports as appropriate+ and co3ordinating their acti)ities as far as is practical to ensure the efficient and effecti)e administration of the re;uirements of the Medicines and <'N= legislation. Bor further information about the <'N= and >RMA re;uirements for obtaining consent to import and or release products controlled under the <'N= legislation+ contact& The Manager+ =perations >n)ironmental Ris8 Management Authorit* New ,ealand 0e)el !+ 1P <ouse %2 Customhouse Hua* P= 1o( !:! ?ellington Telephone& 24# 45: 64%7 Ba(& 24# 45: 64:: ?eb site& http:==www.er%an>.go&t.n>

+01103

'tandards and )harmaco)oeia

?here a product is re;uired to conform or is claimed to conform# to an* particular KstandardL or pharmacopoeial monograph+ it must compl* with all of the re;uirements including test methods+ unless otherwise Nustified# of the current !ersion of that standard or pharmacopoeial monograph. ?here a pharmacopoeial monograph e(ists for an ingredient+ this is considered to be the minimum re;uirements.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

+01+

(onsent not to *e used for 6romotional 6ur)oses

Ministerial consent for the distribution of a new or changed medicine+ or related product is not to be construed as an endorsement of an* claim made for the product. No reference ma* be made to this consent in an* label or ad)ertising+ promotional or other published material about the product.

+013

'u))lying "na))ro.ed Medicines

An Kunappro)ed medicineL is a medicine for which full or pro)isional consent for distribution has not been granted. A general e(emption from the consent pro)isions for new and changed medicines is pro)ided in section %" of the Medicines Act+ permitting the suppl* of an* medicine including an unappro)ed medicine# to a medical practitioner at his.her re;uest+ to treat a particular patient under his.her care. The suppl* must be initiated b* the medical practitioner and the supplier ma* not ad)ertise the a)ailabilit* of the medicine. Medsafe-s web site lists unappro)ed medicines reported to Medsafe as being supplied in New ,ealand+ and includes further information about the responsibilities of the supplier and the medical practitioner and the rights of the patient in)ol)ed in the suppl* of an unappro)ed medicine under the pro)isions of section %. The supplier i.e. the New ,ealand importer or manufacturer# must ha)e a licence issued under the Medicines Act !"6! which allows the suppl* of the medicine+ or be e(empt from this re;uirement under section %7+ and must also maintain complete and accurate records of the information listed below. The records must be stored in a secure and confidential manner in the supplier-s New ,ealand office and be a)ailable for audit b* Medsafe if re;uired. The information to be recorded and stored is& name s# of the medical practitioner s# who re;uested suppl* of the medicine name s# of the patient s# the medicine was re;uired for dose form s# and strength s# of the medicine supplied date s# on which the medicine was supplied name s# of the place s# the medicine was supplied to.

'uppliers of unappro)ed medicines must also notif* the Team 0eader+ Compliance+ Medsafe+ P= 1o( 92!:+ ?ellington+ as soon as practicable after the end of e)er* month in which the medicine has been supplied+ of the following& international non3proprietar* name INN# of the medicine trade name of the medicine pharmaceutical form month and *ear of suppl*

The form for reporting to Medsafe the suppl* of unappro)ed medicines is pro)ided at the end of these guidelines in Appendi( !4.

+015

Medical Ad.ertisements

The Medicines Act !"6! and the Medicines Regulations !"64 control the ad)ertising of therapeutic products including medicines+ related products+ herbal medicines+ medical de)ices+ and methods of treatment. Medical ad)ertisements must compl* with the legislati)e re;uirements. In addition+ such ad)ertisements need to compl* with the KAd)ertising Code of ethicsL and the KCode for Therapeutic

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

Ad)ertisingL in :d!ertising %odes of 1ractice published b* the Ad)ertising 'tandards Authorit* Inc.+ P= 1o( !23759+ ?ellington Tel. 24#45% 569%+ Ba( 24#45! !569. Ad)ertisers intending to publish a medical ad)ertisement in the media including radio+ tele)ision+ newspapers+ maga/ines+ etc.# are strongl* ad)ised first to ha)e the ad)ertisement )etted on behalf of the Ad)ertising 'tandards Authorit* b*& Therapeutic Ad)ertising Pre3)etting 'er)ice TAP'# 4: Tirohunga Dri)e <enderson Auc8land Tel. 2"#6:7 %762 Ba( 2"#6:5 9295

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

'ection 3:

A))lication #y)es

Section summary "o o+tain Ministerial consent to distri+ute a new medicine or related -roduct, the distri+utor must su+mit to Medsafe a GNew Medicine :--licationH ANM:B or GNew Related 1roduct :--licationH ANR1:B, together with su--orting data# 8hen a material change to a -re!iously a--ro!ed medicine or related -roduct is -lanned, the distri+utor or New Zealand manufacturer must notify the 7irector4General of (ealth of the change +y su+mitting a G%hanged Medicine NotificationH A%MNB or G%hanged Related 1roduct notificationH A%R1NB# Legislation to read in conjunction with this section Medicines :ct 1&21 *ection 'C Meaning of DmedicineE, Dnew medicineE, D-rescri-tion medicineE and Drestricted medicineE *ection 20C Restrictions on sale or su--ly of new medicines *ection 2'C Minister may gi!e -ro!isional consent *ection 2.C 7istri+ution of changed medicine restricted

301

When is a Medicine a ANew MedicineBC

The term Knew medicineL is defined in section : of the Medicines Act. In practical terms+ a new medicine is& a medicine for which Ministerial consent for distribution in New ,ealand has not pre)iousl* been granted+ or an appro)ed medicine that has undergone a material change that has resulted in its referral to the Minister under section %4 9# of the Act+ or a medicine that has pre)iousl* been appro)ed but has not been generall* a)ailable in New ,ealand during the fi)e *ears immediatel* preceding the date on which it is proposed to become a)ailable# A medicine is considered to ha)e been Kgenerall* a)ailableL if+ during the rele)ant fi)e *ear period& the product has been sold or offered for sale in New ,ealand on one or more occasions+ or the product has been ad)ertised in New ,ealand as a)ailable for sale+ or the regulator* file for the appro)ed medicine has been updated through either a Changed Medicine Notification CMN# or an application for a labelling e(emption+ or the product has been the subNect of a submission made to P<ARMAC for a tender.

30101

E.idence that a medicine has *een generally a.aila*le

An applicant wishing to show that a product is not a new medicine because it has been Kgenerall* a)ailableL must support that claim b* pro)iding& e)idence of one or more sales during the rele)ant period e.g. in)oice#+ or e)idence of importation e.g. customs clearance form#+ or e)idence of listing in a sales catalogue or price list from the rele)ant period+ or a statement identif*ing regulator* acti)it* for the product+ such as a CMN.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

The claim must be supported b* a declaration from a person in New ,ealand that the e)idence is genuine+ and that an* documents pro)ided are true copies of the original documents. The original documents must be made a)ailable on re;uest.

3010+

6re.iously a))ro.ed medicine that has not *een generally a.aila*le

?hen a sponsor wishes to commence or re3commence distribution of a pre)iousl* appro)ed product that has not been generall* a)ailable in New ,ealand in the last fi)e *ears a New Medicine Application must be submitted+ otherwise+ the medicine ma* onl* be supplied as an unappro)ed medicine under section %" of the Medicines Act see 'ection %.!: of these Guidelines for details#. An appropriate application fee will be re;uired based on the amount of e)aluation and administrati)e wor8 re;uired+ as determined b* the >)aluation Team 0eader. The data must include the elements described in section %! of the Medicines Act. <owe)er+ where the details are the same as those submitted in the original application for consent+ or in an* subse;uent CMN+ it will be sufficient to submit a declaration to that effect. ?here the details differ+ the difference should be detailed and supporting data pro)ided in the same wa* as is re;uired for a CMN. If the change s# is such that the safet* profile of the product ma* ha)e been altered+ the data pac8age should include a report of post3mar8eting sur)eillance from other countries in which the product has been mar8eted.

30103

(om*ination )ac2s of currently a))ro.ed medicines

A new combination pac8 containing two or more currentl* appro)ed medicines pac8aged together constitutes a new medicine and the Minister-s consent for its distribution must be obtained before it ma* be distributed. 'ection % of the Medicines Act !"6! pro)ides a definition of pac8age.

30+

What is a New Acti.e 'u*stance C

A chemical or biological acti)e substance also 8nown as an acti)e pharmaceutical ingredient+ API# is a new acti)e substance+ in line with the >uropean Anion definition+ when it is & a chemical+ biological or biotechnological substance for which Ministerial consent for distribution as a medicine in New ,ealand has not pre)iousl* been granted+ or an isomer+ mi(ture of isomers+ an ester+ a comple( or other deri)ati)e+ or a salt+ of a chemical substance with Ministerial consent for distribution as a medicine in New ,ealand but differing in properties with regard to safet* and efficac*+ or a biological or biotechnological substance for which Ministerial consent for distribution as a medicine in New ,ealand has been granted+ but differing in molecular structure+ nature of the source material or manufacturing process.

303

New Medicine A))lications

A New Medicine Application NMA# is an application under section %2 or %: of the Medicines Act see8ing the Minister-s consent to distribute a new medicine. In practice+ the power to appro)e medicines is delegated to a senior Ministr* of <ealth officer+ referred to as the Minister-s delegate. To facilitate administrati)e processing of applications+ NMAs are di)ided into three t*pes as detailed in 'ubsections :.:.! to :.:.:.

30301

New higher=ris2 medicine a))lications !6

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

A New <igher3ris8 Medicine Application NMA3<# is an application for Ministerial consent to distribute a& new medicine containing a new acti)e substance i.e. a new chemical+ biological or biotechnological entit*# new medicine with pro)isional consent under section %: of the Medicines Act the data re;uirements are different for these applications# medicine with full Ministerial consent under section %2# for which pro)isional consent for distribution under section %: has pre)iousl* been granted new fi(ed combination product containing a prescription medicine new medicine with a new route of administration or no)el pharmaceutical form new inhaled prescription medicine which acts locall* at the bronchial site prescription medicine with a new indication see 'ection : for further e(planation# new )accine new blood product new multi3source biological or biotechnological medicine.

3030+

New intermediate=ris2 medicine a))lications

A New Intermediate3ris8 Medicine Application NMA3I# is an application for consent to distribute a new medicine that does not contain a new acti)e substance and is a& multi3source prescription medicine. CNote that a multi3source biological or biotechnological medicine is a higher3ris8 medicine. The term Kmulti3source medicineL is now used in place of the term Kgeneric medicineL.D Controlled Drug for which a prescription is re;uired medicine with a new but not no)el# pharmaceutical form or a new strength or additional fla)our of an appro)ed prescription medicine prescription medicine with an e(tended indication see 'ection : for further e(planation# inNectable medicine irrigation solution dial*sis solution medical gas.

30303

New lower=ris2 medicine a))lications

A New 0ower3ris8 Medicine Application NMA30# is an application for consent to distribute a new medicine that& is not defined abo)e as a <igher3ris8 or Intermediate3ris8 Medicine+ and ma* be supplied without a prescription i.e. an =TC product#+ and is recommended for indications that are alread* well documented for the acti)e ingredient s#+ and is presented in a pharmaceutical form that is monographed in a pharmacopoeia+ and either contains acti)e ingredients that are the subNect of a pharmacopoeial monograph or contains acti)e ingredients that ha)e a well documented histor* of use in =TC products e.g. as e)idenced b* entries in Martindale etc.# or has acti)e ingredients that are contained in one or more other products mar8eted =TC in New ,ealand. 0ower3ris8 medicines ma* include products re;uired to be sterile e.g. e*e drops#.

!"

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

A product containing a Controlled Drug for which a prescription is not re;uired e.g. pholcodine linctus or a codeine3containing combination analgesic# is e)aluated using the New 0ower3ris8 Medicine assessment procedure+ pro)ided it meets the criteria listed abo)e. New Intermediate3 and 0ower3ris8 Medicine Applications are sometimes referred to as KabridgedL applications+ because the* do not contain the clinical and to(icological data re;uired in a New <igher3 ris8 Medicine Application. New 0ower3ris8 Medicine Applications re;uire less data as the medicine poses a lower3ris8 and can+ therefore+ safel* be subNected to a lower le)el of regulator* control. >ach uni;ue product is the subNect of a separate product appro)al and has its own separate entr* in Medsafe-s Therapeutic Products Database 'MARTI#. A uni;ue product is defined b* its name+ dose form+ acti)e ingredient s#+ strength+ fla)our if applicable# and classification. ?hen an application is made for consent to distribute a new uni;ue product+ a New Medicine Application must be submitted. Reduced data re;uirements and e)aluation fees appl* to New Medicine Applications for products that are closel* related to an e(isting appro)ed product.

305

Referrals under 'ection +5-8/ of the Medicines Act 1<;1

'ection %4 of the Medicines Act sets out restrictions on the distribution of changed medicines. 'ubsection 9 permits the Director3General of <ealth to refer a medicine that is the subNect of a CMN# to the Minister in certain circumstances. 'uch a referral occurs when a CMN is so large or comple( that the changed product should not be allowed to be distributed until the changes ha)e been full* e)aluated. An e(ample of such a change would be a maNor new indication. =nce the CMN has been referred to the Minister under section %4 9# of the Medicines Act+ the application becomes an NMA.

308

(hanged Medicine Notifications and (hanged Related 6roduct Notifications

A Changed Medicine Notification CMN# or Changed Related Product Notification CRPN# is a notification to the Director3General of <ealth b* the sponsor of a product+ under section %4 of the Medicines Act+ of a planned material change to an appro)ed product this includes prescription and non3prescription medicines and related products#+ and the reasons for the change. ?here a medicine or related product is distributed as a complete finished product b* one primar*# sponsor and the same finished product is also distributed b* a second sponsor in a combination pac8 together with another product s#+ both sponsors are responsible to ensure that the second sponsor is informed and the Director3General of <ealth is notified )ia a CMN or CRPN# of an* material changes affecting the medicine or related product in each of its presentations. There should be a commercial agreement between the two sponsors ensuring that the necessar* information is e(changed between them and the necessar* CMNs or CRPNs are lodged with Medsafe. The primar* sponsor ma* lodge the appropriate CMNs or CRPNs for both presentations. A CMN or CRPN is re;uired for each presentation of the product as a consent must be issued for each presentation. If an* change to a product results in a new acti)e ingredient+ new combination of acti)e ingredients+ new strength+ new dose form+ new fla)our or new trade name an NMA or NRPA not a C-N or C)PN# is re;uired. The NMA or NRPA must be 8ept separate from and will be processed separatel* from an* other CMN or CRPN. The Knew productL cannot legall* be distributed until consent has been granted and published in the New Zealand Ga)ette.

30801

Material changes to medicines and related )roducts

A material change to a medicine or related product ma* re;uire e)aluation in which case an e)aluation fee is pa*able# or be self3assessable in which case an administrati)e fee is pa*able#. Assessable

%2

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

changes are notified through a CMN or CRPN and consent must be obtained before the change is made. As8 Medsafe for ad)ice if there is doubt about whether a proposed change is notifiable or not. =ften one change in a product leads automaticall* to other changes e.g. a change in formulation will often result in changes in manufacture+ ;ualit* control and stabilit*#. Details of the )arious t*pes of assessable and self3assessable changes and the applicable fees are gi)en in the CMN and CRPN forms see Appendices 9 3 5#. The forms include common material changes and changes conse;uent to these# and are designed to be as comprehensi)e as possible. If an intended change is not included in the rele)ant form+ see8 ad)ice from Medsafe. Bor a self3assessable change+ there is no re;uirement to obtain consent prior to ma8ing the change. <owe)er+ the notification must precede the change. The onus is on the applicant to ensure that data to support the change are held and could be made a)ailable on re;uest. 'uch changes are to be notified using the same CMN or CRPN form as used for notif*ing assessable changes. Medsafe carries out random audits of self3assessable changes and+ where an* significant problems are identified+ the sponsor is re;uired to rectif* these. ?here a CMN or CRPN rather than a 'ACN should ha)e been submitted+ the sponsor is as8ed to submit this.

%!

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

'ection 5:

Fees

Section summary "his section sets out the fees a--lied to a--lications and notifications for new and changed -roducts# Legislation to read in conjunction with this section Medicines Regulations 1&2., :mendment No# . AFeesB

501

E.aluation Fees

Amendment 4 to the Medicines Regulations !"64 sets out the fees for e)aluation of New Medicine or Related Product Applications and Changed Medicine or Related Product Notifications. #ees are (ST7 inclusi&e. The fees schedule appl*ing to applications and notifications is gi)en in Appendi( ! and guidance for calculating the fees for specific t*pes of new and changed products are gi)en in the rele)ant new medicine and related product application forms see Appendices %3:# and changed medicine and changed related product notification forms see Appendices 935#

50101

New medicine or related )roduct a))lications

The fee for e)aluation of a New Medicine Application is based on the amount of effort in)ol)ed in e)aluating the application. The fee is therefore greater for a medicine containing a new acti)e substance than for a new multi3source medicine. The fee is further reduced in the case of an application for consent to mar8et a new dose form+ strength or fla)our of a product. A product is considered to be a separate product and+ therefore+ a new medicine or new related product if it has a different name+ acti)e ingredient+ strength+ dose form+ fla)our or classification from a pre)iousl* appro)ed product. >ach product is the subNect of a separate product appro)al+ has a separate file number and has its regulator* details recorded in a separate entr* in Medsafe-s Therapeutic Product Database 'MARTI#. Note that+ in this conte(t+ a different pac8 si/e does not constitute a different strength. ?hen consent is sought for the distribution of a new or additional product that is substantiall* the same as a pre)iousl* appro)ed product such as an additional name or strength#+ a reduced data pac8age is re;uired to be e)aluated. The fee for e)aluation is based on the amount of e)aluation effort re;uired to assess the differences between the old and new products. ?hen simultaneous applications are lodged for two or more dose forms of a product+ the KparentL dose form will be that which would on its own attract the greatest fee and the KadditionalL dose forms will be those that would attract the lower fees. Bor e(ample+ if an application was for a tablet and an inNection of a particular medicine+ then the tablet would be the parent dose form and the inNection would be the additional dose form. If an application was for more than one dose form and it would ma8e no difference to the fees which dose form was chosen as parent+ then an* one of them could be selected as the parent dose form for the purpose of the application.

5010+

(hanged medicineDrelated )roduct notifications

%%

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

The fees for e)aluation of Changed Medicine.Related Product Notifications reflect the a)erage amount of e)aluation effort in)ol)ed in assessment of the data. The amount of e)aluation effort depends on the number of changes being made+ the nature of the changes+ and the number of separate products to which the changes appl*. The fees also co)er the administrati)e wor8 in)ol)ed in updating and maintaining Medsafe records. Same change(s) to multiple products ?hen an identical change or set of changes is made to two or more products at the same time+ the e)aluation effort in)ol)ed in assessing the change usuall* does not ha)e to be repeated for each product. There is+ howe)er+ a cost associated with the administrati)e processing of each application recei)ed. This administrati)e cost is incurred regardless of the amount of e)aluation effort in)ol)ed. To co)er this cost+ an Kadministration onl*L fee applies to applications for which no e)aluation effort is re;uired. In no case can the total fee for changes to a product e(ceed the fee for an NMA or NRPA for the same t*pe of product.

50105

'elf=assessa*le change notifications

An Kadministration onl*L fee applies to self3assessable changes. ?hen the same self3assessable change is made to multiple products+ the Kadministration onl*L fee applies to each product affected b* the change. No fee is pa*able for self3assessable changes notified along with a CMN or CRPN for which e)aluation of data is re;uired and a fee is pa*able+ e(cept in the case of a data sheet for which the changes are not conse;uential to an* other change included in the CMN or CRPN. In this case an additional 'ACN fee is re;uired for the changes to the data sheet.# If a 'ACN is audited and a proper CMN or CRPN is re;uired to be submitted the full CMN or CRPN fee for the change s# must be paid. The 'ACN fee alread* paid is used to co)er the administration and auditing of the 'ACN and is not treated as part of the CMN or CRPN fee.

50+

Administration

Pa*ment to co)er the fee or e)idence that the fee has been paid# must accompan* e)er* application or notification. Bees for NMAs+ NRPAs+ CMNs and CRPNs+ clinical trial appro)als and Certificates of Pharmaceutical Products ma* be paid either b* che;ue or b* direct credit to the Ministr* of <ealth ban8 account. Antil further notice+ all other Medsafe fees must be paid b* che;ue. Credit card pa*ments are not accepted for an* Medsafe fees. If pa*ment is b* che;ue+ the che;ue should be made out to the Ministr* of <ealth. The Ministr*-s G'T number for accounting purposes is !43%"23:6".

%:

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

Bor direct credit pa*ments+ the Ministr*-s ban8 account details are as follows& 2an6 na%e and address: ?estpac Trust+ N, Go)ernment 1ranch ?ellington+ New ,ealand 2an6 account na%e: Ministr* of <ealth 2an6 account nu%1er: 2:3224"3222!629326

To enable eas* identification of pa*ments the following information should appear on Medsafe-s ban8 statements&

Particulars
Compan* name+ abbre)iated or coded if necessar* to fit a)ailable bo(es#

Code
TT92 number for CMNs and CPPs#

Reference
QCode and medicine name#

BCodes: NMA for new medicine application NRPA for new related product application CMN for changed medicine notification CRPN for changed related product notification CT for clinical trial application CPP for Certificates of Pharmaceutical Product Bree 'ales Certificate#

&m)ortant Notes: !. The full amount in RN, e(clusi)e of ban8 charges must be paid. %. 'eparate transactions are re;uired for each application or notification. ?here a group of two or more dose forms is in)ol)ed+ one transaction co)ering the grouped applications or notifications is re;uired. :. A remittance slip or a co)ering letter# with full pa*ment details must be included with the application or notification 4. No liabilit* can be accepted b* the Ministr* of <ealth for pa*ments that do not reach our ban8 account. It is the pa*er-s responsibilit* to follow up an* pa*ments that ha)e not been recei)ed b* the Ministr*. The Ministr* will onl* be able to confirm whether or not a pa*ment has been recei)ed. Medsafe-s letter ac8nowledging receipt of an application or notification includes confirmation of receipt of the fee. If an application is not accompanied b* the appropriate fee+ the applicant is informed that an additional pa*ment is re;uired. Processing of an application does not commence until the appropriate fee has been paid in full. ?hen an applicant pa*s a fee greater than re;uired+ the surplus will be refunded b* che;ue as soon as this can be arranged.

503

Fee Wai.ers

The legislation allows for the fee to be wai)ed+ either partiall* or completel*+ after ta8ing into consideration the comple(it* of the application and the amount of time re;uired to complete the e)aluation. Bees ma* also be wai)ed in the interests of public health. In certain circumstances e.g. in the case of )er* low )olume.)alue sales# a partial or complete wai)er of fees ma* be appropriate. 'uch fee wai)ers will be considered on their merits on a case3b*3case basis. An applicant who considers a wai)er appropriate should submit a written re;uest and e(planation to the >)aluation Team 0eader for consideration.

%4

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

'ection 8:

Administrati.e 6rocedures

Section summary "his sectionC e>-lains who e!aluates different ty-es of a--lications descri+es the !arious -hases in the e!aluation -rocess sets out MedsafeEs -erformance targets for the e!aluation of new and changed medicine and related -roduct a--lications Legislation to read in conjunction with this section Medicines :ct 1&21 *ection 'C Meaning of DmedicineE, Dnew medicineE, D-rescri-tion medicineE and Drestricted medicineE *ection 2C :d!isory and technical committees *ection &C Medicines %lassification %ommittee *ection 10C Medicines Re!iew %ommittee esta+lished *ection 20C Restrictions on sale or su--ly of new medicines *ection 21C :--lications for MinisterEs consent *ection 2'C Minister may gi!e -ro!isional consent *ection 2&C />em-tion for medicine re uired +y medical -ractitioner *ection 10&C Relationshi- with Misuse of 7rugs :ct 1&0$ Medicines :mendment :ct 1&&. First *chedule to the Medicines Regulations 1&2. I :mendments AMedicines %lassificationB Misuse of 7rugs :ct 1&0$ I Regulations

801
80101

E.aluation 6rocesses for A))lications and Notifications


New higher=ris2 medicine a))lications

Most New <igher3ris8 Medicine Applications are e)aluated b* members of the Medicines Assessment Ad)isor* Committee MAAC#. ?here appropriate+ some ma*+ instead+ be e)aluated b* e(ternal e)aluators contracted b* Medsafe+ or b* Medsafe-s own e)aluation staff. Bollowing this e)aluation+ the full MAAC re)iews and discusses the e)aluation reports and ma8es a recommendation to the Minister of <ealth-s delegate to grant or decline consent+ or the Committee defers a decision pending satisfactor* responses to an* ;uestions raised. The MAAC ma* recommend pro)isional consent to distribute a medicine under section %: of the Medicines Act where it belie)es that the medicine should be a)ailable but there is insufficient e)idence of safet* and.or efficac* to allow full consent. Most applications for pro)isional consent under section %: and most new indications for currentl* distributed higher3ris8 medicines are also considered b* the MAAC. A Knew indicationL usuall* is an e(tension of indications to the treatment of a condition not conse;uential to the indications alread* appro)ed+ or the treatment of a condition affecting another s*stem of the bod*. All e(tended indications for alread* appro)ed products including e(tensions of currentl* appro)ed indications to include special populations+ e.g. paediatric+ geriatric+ etc.# are considered to be Knew indicationsL. As a general rule+ all new and e(tended indications will be referred under section %4 9# as a new medicine application.

%9

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

Members of the MAAC are appointed b* the Minister of <ealth. The terms of reference of the Committee are to& assess and ad)ise on the efficac*+ safet* and ;ualit* of new medicines recommend the classification of new medicines consider and ad)ise the Minister on the suitabilit* of medicines for distribution in New ,ealand consider and ad)ise the Minister on an* matters regarding new medicines or the distribution of medicines.

The MAAC normall* meets four times per *ear+ usuall* earl* in March+ Pune and 'eptember+ and in late No)ember or earl* December. >)aluation of the labelling and data sheet of medicines considered b* the MAAC is usuall* carried out b* Medsafe e)aluators in liaison with the Committee. An* communication between the sponsor and the MAAC regarding an* aspect of an application must be carried out through the MAAC 'ecretar*.

8010+

New intermediate= and lower=ris2 medicine and related )roduct a))lications

Medsafe e)aluators assisted b* e(ternal e)aluators where appropriate# assess New Intermediate3 and 0ower3ris8 Medicine and New Related Product Applications. These applications are allocated to one of the two e)aluation KstreamsL. =ne stream e)aluates all applications for which there is an e(tended time3frame. These are& New Intermediate3ris8 Medicine Applications NMAs for inNectable medicines e)en though these ma* be classified as pharmac*3onl* medicines# Medical gases CMNs for Intermediate3ris8 medicines referred under section %4 9# of the Medicines Act. As a general rule+ all new and e(tended indications will be referred under section %4 9#.

The other stream e)aluates all applications for which there is a shortened time3frame. These are& New 0ower3ris8 Medicine Applications New Related Product Applications InNectable diluents e.g. water for inNection or normal saline# presented separatel* from products containing acti)e ingredients CMNs for prescription and non3prescription medicines and related products

80103

(hanged medicine notifications and changed related )roduct notifications

CMNs+ whether for prescription or non3prescription medicines+ and CRPNs are usuall* assessed b* Medsafe e)aluators but ma* sometimes be sent to e(ternal e)aluators. Bollowing e)aluation+ a decision is made whether to accept the change+ or re;uest more information from the applicant. 'elf3assessable Change Notifications 'ACNs# undergo administrati)e processing e.g. filing and updating of Medsafe-s Therapeutic Product Database 'MARTI#+ but do not re;uire e)aluation.

80+

6riority Assessment of New Medicine A))lications

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

80+01

(riteria for )riority assessment

The two criteria for eligibilit* for priorit* assessment of an NMA are significant clinical ad)antage or significant potential cost sa)ings to the ta(pa*er. -1/ 'ignificant clinical ad.antage Re;uests for priorit* assessment on the basis of significant clinical ad)antage will be considered for New <igher3ris8 Medicine Applications for products containing new acti)e substances. $accines for the pre)ention of diseases are treated in the same wa* as other agents for the treatment of diseases. Cost sa)ing does not constitute a significant clinical ad)antage+ hence will not be ta8en into account when deciding whether a product meets the clinical criteria for priorit* assessment. The sponsor of a medicine ma* re;uest priorit* assessment if& the medicine is the subNect of a New <igher3ris8 Medicine Application+ and the acti)e ingredient of the medicine is a new acti)e substance+ and the medicine is indicated for the treatment or diagnosis of a serious+ life3threatening or se)erel* debilitating disease or condition for which other treatment options are limited+ and data demonstrating the effect of the medicine on clinical outcomes is submitted with the application. Re;uests for priorit* assessment can onl* be made b* the New ,ealand sponsor or distributor of the product. 'ponsors are encouraged to pro)ide support for claims of significant clinical ad)antage b* submitting material such as letters of support from clinicians and consumer support groups. The >)aluation Team 0eader and Clinical Ad)isor s# decide which applications are accepted for priorit* assessment on the basis of significant clinical ad)antage. -+/ 'ignificant )otential cost sa.ings A re;uest for priorit* assessment of a medicine on the basis of potential cost sa)ings can normall* onl* be made b* P<ARMAC. 'uch re;uests are considered b* the Minister-s delegate who+ where appropriate+ instructs Medsafe to underta8e a priorit* assessment of the application.

80+0+

6rocessing of )riority assessment a))lications

Applications that ha)e been accepted for priorit* assessment on clinical grounds+ or are accompanied b* an instruction from the Minister-s delegate directing that the* be gi)en priorit* on cost3sa)ing grounds+ will be processed earlier and faster than normal applications. =nce an application has been accepted for priorit* assessment on clinical grounds+ the application is placed on the agenda for the ne(t MAAC meeting pro)ided there is sufficient time for the e)aluation reports to be prepared and considered b* members. Bollow3up actions resulting from recommendations from MAAC are completed in the usual wa*. <owe)er+ when a response to a re;uest or ;uer* is recei)ed from the applicant+ its assessment is also gi)en priorit*. The internal assessment of the data sheet and labelling recei)es similar priorit*. Most applications undergoing priorit* assessment on cost3sa)ing grounds will be New Intermediate3ris8 Medicine Applications e)aluated b* Medsafe e)aluators. ?here a priorit* assessment on cost3sa)ing grounds relates to a medicine that is re)iewed b* the MAAC+ the process is as described abo)e for priorit* assessment on clinical grounds. Bor an internall*3e)aluated product gi)en priorit*+ the application is allocated to an e)aluator and becomes that e)aluator-s ne(t piece of new wor8. In a similar wa*+ when a response relating to a

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

priorit* assessment is recei)ed from an applicant+ that response becomes the ne(t piece of follow3up wor8 underta8en b* the e)aluator.

803

6hases of the E.aluation 6rocess

The e)aluation process for new and changed medicine and related product applications and notifications is di)ided into phases+ each with a specific performance target. Administrati)e processing of an application cannot commence until a )alid application has been lodged. A )alid application is an application submitted in an appropriate format+ with an appropriate data pac8age+ and accompanied b* the appropriate fee.

80301

New higher=ris2 medicine a))lications

The administrati)e process for New higher3ris8 medicine applications is di)ided into three phases as follows& Phase 1: Receipt and acknowledgement of the application This phase consists of the following processes. !. Medsafe recei)es the application and appropriate fee. %. The 'upport =fficer creates a new file and Therapeutic Product Database 'MARTI# entr*+ and sends an ac8nowledgement letter to the applicant. :. The 'upport =fficer forwards the application to the ?or8flow Co3ordinator. 4. The ?or8flow Co3ordinator assigns the application to the MAAC and forwards the file to the MAAC 'ecretar*. Completion of Phase ! is mar8ed b* the MAAC 'ecretar* recei)ing the application for processing b* the MAAC. Phase 2: Evaluation The products to be considered at an MAAC meeting are determined about : months before the meeting. A t*pical agenda includes about !% new medicines including new chemical or biological entities and new dose forms or combinations of pre)iousl* appro)ed medicines#+ a number of new or e(tended indications for pre)iousl* appro)ed medicines+ and reconsideration of se)eral medicines for which appro)al was pre)iousl* deferred and sponsors ha)e pro)ided responses to the issues raised b* the MAAC. The new medicines t*picall* include one or two products for which priorit* assessment has been granted+ se)eral products for which o)erseas e)aluation reports are or will be a)ailable for the Committee-s use+ and se)eral products for which no o)erseas reports are a)ailable. The actual mi( of applications is arranged to ensure that ma(imum use can be made of o)erseas reports and that all applications can flow smoothl* through the ;ueue without unnecessar* dela*s and that the* can reach the MAAC not more than !6 months after submission. A tentati)e agenda is set about !: wee8s before the meeting. Asuall* one place on the agenda is sa)ed for an* late3coming Kfast3trac8edL application. The agenda is closed !2 wee8s before the meeting. The MAAC 'ecretar* ad)ises the applicant about !%3!: wee8s before the Committee meeting that the application is scheduled for consideration b* the MAAC at the forthcoming meeting. Asuall* at the same time+ further copies of the Part I sufficient for each MAAC member e(pected to be at the meeting to ha)e a cop*# and the pi)otal clinical trial reports from Part I$ of the application dossier are re;uested for the Committee-s use. The amount of additional data re;uested from the sponsor depends upon the a)ailabilit* or otherwise of suitable o)erseas e)aluation reports. ?here the Committee or

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

indi)idual members e)aluating the data find it necessar* to access data not pro)ided at this time+ the 'ecretar* ma* re;uest the additional )olumes from the applicant. Note: If the e(tra copies of data supplied for Committee use at this time or later in response to ;ueries raised b* the MAAC# include material not pre)iousl* supplied with the original application+ an e(tra cop* of this material should also be supplied and clearl* identified# for addition to Medsafe-s cop* of the application and supporting data. ?hene)er possible+ to reduce unnecessar* duplication of effort+ an e)aluation report is obtained from another regulator* agenc* with whom New ,ealand has a Memorandum of Anderstanding MoA# or similar agreement. Reports are onl* obtained from agencies that approach medicine regulation in such a manner that New ,ealand regulators can ha)e confidence in the ;ualit* of their e)aluation process. The MAAC see8s to obtain copies of suitable o)erseas e)aluation reports and compan* responses to an* issues raised in those reports# to assist it in its own assessment of the medicines it considers. If o)erseas reports are used b* the MAAC+ the Committee does not simpl* adopt the conclusions of the o)erseas e)aluators but e(amines the reports and sufficient raw data together with an* additional information pro)ided b* the sponsor to enable it to form its own independent assessment of the product. There is a MoA currentl* in place with the Therapeutic Goods Administration TGA# in Australia. The TGA routinel* pro)ides Medsafe with copies of its e)aluation reports prepared for the Australian Drug >)aluation Committee AD>C#+ and Medsafe routinel* supplies the TGA with copies of e)aluation reports prepared for the MAAC. This e(change does not include copies of additional data submitted b* companies in response to issues raised during the e)aluation. Medsafe also has access to the reports produced b* >uropean authorities for the >uropean Medicines >)aluation Agenc* >M>A# and its Committee for Proprietar* Medicinal Products CPMP#. Ander a special agreement with the >M>A+ where a product has been considered b* the >M>A.CPMP for distribution in the >uropean Anion under its centralised procedure+ the compan* responsible for the product is free to release a cop* of the full CPMP e)aluation report s# to regulator* authorities in P>R member countries outside of the >uropean Anion as soon as the CPMP has gi)en a recommendation for appro)al of the product. 'ponsors of products to be considered b* the MAAC should arrange for a cop* of these CPMP reports to be forwarded to the MAAC 'ecretar* as soon as the CPMP recommendation is made. Please note that >uropean Public Assessment Reports >PARs# are onl* summaries of the >M>A e)aluation and appro)al process and are not suitable for use b* Medsafe or the MAAC. ?hile TGA reports are obtained directl* from the TGA+ the applicant is normall* as8ed to suppl* along with additional copies of data from the application dossier# se)eral e(tra copies of an* a)ailable TGA and.or >uropean e)aluation report along with copies of an* additional data submitted to the o)erseas agenc* ies# concerned to satisf* that agenc*-s re;uirements for further information or changes to the product or supporting data. ?here no suitable o)erseas e)aluation report is a)ailable+ or li8el* to be a)ailable within a reasonable time+ the application and dossier of supporting data are e)aluated in full b* MAAC members or contracted e)aluators for the MAAC. The MAAC 'ecretar* recei)es the o)erseas and.or New ,ealand e)aluation report s# and distributes them to Committee members. The MAAC then re)iews the e)aluation report s# at a Committee meeting and ma8es a recommendation to the Minister of <ealth-s delegate to grant or decline consent+ or it defers ma8ing a recommendation until additional information has been recei)ed and re)iewed. Bollowing the Committee-s consideration of the application+ a summar* briefing of the outcome is forwarded to the Minister-s delegate. The briefing will also indicate whether Medsafe supports the

%"

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

recommendation of the Committee. In the rare e)ent that Medsafe disagrees with the MAAC recommendation+ the Minister-s delegate will consider the conflicting recommendations before ma8ing a final decision. The MAAC 'ecretar* informs the applicant in writing of the MAAC recommendation+ normall* within % wee8s of the meeting. $erbal information about the outcome of the MAAC-s deliberations will not be gi)en and should not be sought# prior to receipt of the 'ecretar*-s letter. If the MAAC has recommended that consent be declined+ the applicant is gi)en the option of either withdrawing the application or submitting arguments and.or additional data for consideration b* the MAAC before a final decision is made. If the application is not withdrawn and no additional information is submitted+ and the Minister-s delegate accepts the MAAC-s recommendation+ the applicant then has %6 da*s from receipt of the formal notification that the application has been declined in which to lodge an appeal and pa* the re;uisite fee. 'uch appeals are referred to the Medicines Re)iew Committee MRC#. The MRC does not re)iew the technical data related to the product concerned+ but re)iews the process followed+ to ensure that the application has been considered fairl* and ade;uatel*. Bor products for which consent has been recommended+ the MAAC 'ecretar* e)aluates the draft label s# and data sheet and ensures that an* recommendations b* the MAAC are agreed with the applicant and incorporated. The 'ecretar* then sends a cop* of the e)aluation reports and the draft Therapeutic Product Database Report to the applicant. The applicant should chec8 the details on the database report carefull* for accurac* and ad)ise the MAAC 'ecretar* immediatel* if an* changes are re;uired before the report becomes the Kofficiall* agreed particularsL about the product concerned. Completion of Phase % is mar8ed b* the finalising of the labels+ data sheet and details in Medsafe-s Therapeutic Product Database 'MARTI#.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

Phase : !onsent process Phase : applies onl* to medicines for which consent is to be granted and consists of the following processes& !. The 'ecretar* forwards the product file to the 'upport =fficer who drafts the New Zealand Ga)ette notice of Ministerial consent. Note that ga/ettal applies to new medicines+ new presentations of medicines+ and appro)als of CMNs for new indications for medicines referred as NMAs under section %4 9# of the Medicines Act. %. The Minister-s delegate signs the draft New Zealand Ga)ette notice+ thus formall* consenting to the distribution of the product in New ,ealand :. The 'upport =fficer submits the New Zealand Ga)ette notice for publication and completes the Therapeutic Product Database 'MARTI# entr* showing the date of consent following publication of the notice in the Ga)ette# and forwards copies of the New Zealand Ga)ette notice and the finalised database report to the applicant. The distributor ma* legall* distribute and promote the product from the date of publication of the New Zealand Ga)ette notice. The date of consent is the date of publication of the notice+ not the date on which the notice was signed b* the Minister-s delegate. Completion of Phase : is mar8ed b* dispatch of copies of the New Zealand Ga)ette notice and finalised database report to the applicant.

8030+

New intermediate= and lower=ris2 medicine and related )roduct a))lications

The administrati)e process for New Intermediate3 and 0ower3ris8 Medicine Applications and New Related Product Applications is di)ided into three phases as follows& Phase 1: Receipt and acknowledgement of the application This phase consists of the following processes& !. Medsafe recei)es the application and appropriate fee %. The 'upport =fficer creates a new file and database entr* and sends an ac8nowledgement letter to the applicant :. The 'upport =fficer forwards the application to the ?or8flow Co3ordinator 4. The ?or8flow Co3ordinator assigns the application to the appropriate e)aluation stream and forwards the file to an e)aluator. Completion of Phase ! is mar8ed b* the forwarding of the application to an e)aluator for assessment. Phase 2: Evaluation The e)aluator assesses the application and supporting data and completes an e)aluation report. If there are no outstanding issues the application mo)es directl* to Phase :. If+ on the other hand+ additional information needs to be supplied or changes need to be made to the product or data+ the e)aluator will inform the applicant. The applicant ma* also be sent a cop* of the draft e)aluation report at this stage. The applicant then collates and forwards to the e)aluator a response to an* re;uest for additional information or changes. The e)aluator e)aluates the additional information when supplied and prepares a final report on the product. There can be se)eral c*cles of additional information being re;uested+ pro)ided and e)aluated. <owe)er+ the performance target for this phase relates to the time from receipt of the first response from the applicant to completion of the e)aluation of that response. The e)aluator completes the final e)aluation report and forwards this to the e)aluation stream 'enior Ad)isor for re)iew.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

The e)aluation stream 'enior Ad)isor re)iews the e)aluator-s report and+ if necessar*+ the report is amended. If the product is a multi3source medicine in a solid oral dose form or another form that ma8es it a potential candidate for specific inclusion in the list of Interchangeable Multi3source Medicines+ the final e)aluation report is forwarded to the Generics 'ubcommittee of the MAAC for re)iew before a final decision is made to recommend consent. In the case of an intermediate3ris8 medicine but not a lower3ris8 medicine or a related product# the e)aluator sends a cop* of the completed e)aluation report+ the draft Therapeutic Product Database Report+ and a letter stating+ if appropriate+ that all issues are resol)ed or indicating an* re;uirements to be fulfilled or data to be submitted after appro)al of the product# and that the product will be recommended for consent. If a labelling e(emption has been granted this will be indicated in the letter. The applicant should chec8 the details on the database report carefull* for accurac* and ad)ise the e)aluator immediatel* if an* changes are re;uired before the report becomes the Kofficiall* agreed particularsL about the product concerned. If there are significant obstacles to appro)al of the product+ the applicant ma* withdraw the application or Medsafe ma* forward the application and report to the MAAC for ad)ice on whether the application should be declined. Completion of Phase % is mar8ed b* the finalising of the recommendation for consent or decline and for products to be appro)ed for distribution in New ,ealand# forwarding of the product file to the 'upport =fficer for drafting of the New Zealand Ga)ette notice. Phase : !onsent process This phase consists of the following processes& !. The 'upport =fficer drafts the New Zealand Ga)ette notice. %. The Minister-s delegate signs the draft New Zealand Ga)ette notice+ thus formall* consenting to the distribution of the product in New ,ealand. :. The 'upport =fficer submits the New Zealand Ga)ette notice for publication 4. The 'upport =fficer submits the New Zealand Ga)ette notice for publication and completes the database entr* showing the date of consent following publication of the notice in the New Zealand Ga)ette# and forwards a cop* of both the New Zealand Ga)ette notice and the finalised database report to the applicant. The distributor ma* legall* commence distribution and promotion of the product as from the date of publication of the New Zealand Ga)ette notice. Completion of Phase : is mar8ed b* dispatch of the New Zealand Ga)ette notice and finalised database report to the applicant.

80303

(hanged medicine or related )roduct notifications

Changed Medicine and Related Product Notifications proceed through a process similar to the first two phases of the process as described for NMA3Is and NMA30s in 'ection 9.:.% abo)e# but completion of Phase % is mar8ed b* the issue of a consent letter b* the e)aluator rather than publication of a Ga)ette notice# and an updated database report.

805

Re?uests for Further &nformation

At completion of the initial e)aluation of an application the applicant ma* recei)e a re;uest for additional information arising from the e)aluation. A response to the re;uest should be sent as ;uic8l* as possible. If a full response is li8el* to ta8e longer than an* deadline gi)en in the letter re;uesting the

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

information+ the applicant should send an interim response indicating when the information will be a)ailable and re;uesting an e(tension of the deadline. Applicants should ensure that each issue re;uiring further information has been responded to+ e)en if it is necessar* to pro)ide onl* an interim response and an underta8ing to suppl* additional data b* a specified date. 4&aluation o+ additional in+or%ation will not nor%all! co%%ence until a +ull response has 1een recei&ed.

808
80801

$utcomes of the E.aluation 6rocess


Full consent

Bull consent is Ministerial consent for the distribution of a medicine or related product in New ,ealand without an* special conditions. Bull consent ta8es effect from the da* the consent is published in the New Zealand Ga)ette#

8080+

6ro.isional consent

Pro)isional consent for distribution of a new medicine ma* be granted under section %: of the Medicines Act where there is insufficient safet* or efficac* information to Nustif* full consent but the MAAC accepts that there is a clinical need for the medicine to be a)ailable in New ,ealand. This allows limited access to a medicine where the potential benefit is considered greater than the ris8 of non3treatment. Bor e(ample+ a medicine that does not ha)e long3term safet* data a)ailable ma* show potential in treating a rare fatal condition for which there is no alternati)e treatment. ?here onl* pro)isional consent is granted for the distribution of a medicine+ this fact+ along with an* conditions imposed upon its distribution+ should be included in the data sheet for the product. There are two situations where pro)isional consent ma* be granted& -1/ $riginal a))lication is for )ro.isional consent If an NMA is onl* for pro)isional consent at the time of lodging the NMA and the MAAC considers that the data support onl* pro)isional consent+ pro)isional consent onl* will be granted. The applicant ma* later submit additional or updated data and an application for upgrading of the appro)al to full consent. If this second application and supporting data are submitted within % *ears of the pro)isional consent being granted+ an additional fee to bring the total up to that appl*ing to an NMA for full consent will be pa*able before full consent is considered. If the application for upgrading of the appro)al to full consent is recei)ed after e(pir* of the pro)isional consent+ an additional fee e;ui)alent to that appl*ing to a fresh NMA for full consent will be re;uired. Alternati)el*+ if the MAAC considers that the data submitted with the first application support full consent+ such consent will be offered to the applicant but an additional fee to bring the total up to that appl*ing to an NMA for full consent will be pa*able before full consent is granted. -+/ $riginal a))lication is for full consent If an NMA is for full consent and is supported b* a full dossier of data and accompanied b* a full NMA fee but+ after re)iewing the data+ the MAAC or Medsafe concludes that the data onl* support pro)isional consent+ onl* such consent will be granted. No part of the fee will be refunded. <owe)er+ if the applicant later submits additional data re;uired to support full consent and re;uests upgrading of

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

the appro)al to full consent+ this application will be considered without an additional fee if submitted prior to the e(pir* of the pro)isional consent. If the application for upgrading of the appro)al to full consent is recei)ed after e(pir* of the pro)isional consent+ an additional fee e;ui)alent to that appl*ing to an NMA for full consent will be re;uired. Pro)isional consent ma* be granted for a period of up to two *ears+ and the a)ailabilit* of the medicine is usuall* restricted to certain prescribers or target patient populations. An application for renewal of the consent can be made and a renewal fee paid# prior to the e(pir* of the two3*ear period. <owe)er+ an application for full consent can be made at an* time if the re;uired data become a)ailable. The MAAC assesses all applications for pro)isional consent. A recommendation to decline an application for pro)isional consent ma* be due to& lac8 of e)idence of ade;uate therapeutic efficac* unNustifiable safet* ris8 due to 8nown problems with the manufacturing process or formulation inade;uate information on which to assess ris8 ris8 of non3treatment of the condition being less than the ris8s in)ol)ed in use of the product+ or alternati)e preferred treatments of 8nown ris8 and efficac* are a)ailable.

80803

!ecline

Bor all NMAs and NRPAs it is usual practice for Medsafe e)aluators or the MAAC to 8eep re;uesting information from the applicant+ or changes to the product+ until all issues are satisfactoril* resol)ed. If+ after e(hausti)e re;uests+ the applicant refuses or is unable to pro)ide the re;uired information or an assurance that an* re;uired changes to the product will be made#+ then a recommendation is normall* made b* the MAAC to the Minister-s delegate to decline the application. The applicant is notified of the terms of the recommendation to decline and the reasons. The applicant is gi)en %6 calendar da*s after recei)ing the notice+ to lodge a written obNection to the recommendation. 'uch obNections are considered b* the Medicines Re)iew Committee+ constituted under sections !2 3 !: of the Medicines Act !"6!. This Committee can recommend that the application be declined+ accepted+ or referred bac8 to the MAAC. There is no pro)ision in the legislation for Medsafe to decline a CMN. <owe)er+ if the change notification is not satisfactor*+ and the applicant is unable to satisfactoril* answer the ;uestions raised during e)aluation+ the applicant ma* be as8ed to withdraw the notification+ or it ma* be referred to the Minister-s delegate under section %4 9# of the Medicines Act+ thus ma8ing it an NMA. In either case+ the applicant ma* not distribute the changed medicine.

80805

Withdrawal

The applicant is encouraged to withdraw an application or notification when there is no longer a desire to obtain consent to distribute the medicine+ or the applicant is unable to satisfactoril* answer ;uestions raised in the e)aluation process. In these instances+ the applicant should re;uest in writing that the application or notification be withdrawn. There is no refund of the application fee and no return of the data submitted.

80808

Re.ocation of consent or withdrawal from the mar2et

Re)ocation of consent for the distribution of a medicine or related product ma* be initiated b* Medsafe or b* the sponsor. This ma* be for safet* reasons or for issues affecting intellectual propert* of information used in the e)aluation process. 'uch re)ocation must be notified in the New Zealand Ga)ette# If a sponsor wishes to ha)e consent re)o8ed+ the sponsor should inform the Manager+ Medsafe accordingl* in writing gi)ing reasons for the decision.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

Alternati)el*+ a sponsor ma* wish to withdraw a product from the mar8et without ha)ing consent for distribution formall* re)o8ed. In this case the sponsor should inform the Manager+ Medsafe accordingl* prior to the withdrawal ta8ing effect. The withdrawal will then be recorded in Medsafe-s database. The sponsor ma* subse;uentl* resume distribution of the product at an* time up to 9 *ears after the withdrawal. Medsafe must be informed of the resumption of distribution before it ta8es place. If a product remains off the mar8et for more than 9 *ears consent lapses and can onl* be reacti)ated through submission of a new medicine application.

809

!ata*ase Re)ort

=nce consent is granted+ an updated Therapeutic Product Database Report TPDR# will be forwarded to the applicant. This report pro)ides a record of the appro)ed particulars of the product. It should be retained and used as a reference for subse;uent regulator* acti)ities.

80:

6rocessing #imes for A))lications and Notifications

Processing times ta8en b* Medsafe for the different phases of the e)aluation and consent process are shown in the following table. The times stated are those ta8en Cin calendar da!s< to complete the processes concerned for the %aDorit! .,E< o+ applications and noti+ications during the !%3month period Pul* !""" to Pune %222. These times are gi)en to pro)ide applicants with a general guide to the times that Medsafe-s processing of the different t*pes of applications and notifications can be e(pected to ta8e. No data are gi)en for processes o)er which Medsafe has no control.

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6rocessing times for ;,E of a))lications and notifications


Phase Aigher7ris6 New -edicine pplications and S2".$ C-Ns Inter%ediate7ris6 New -edicine pplications and S2".$ C-Ns Lower7ris6 New -edicine F New )elated Product pplications and S2".$ C-Ns Changed -edicine F )elated Product Noti+ications C1ut not S2".$ C-Ns<

)eceipt and ac6nowledge%ent Init ial e&al uati on

Application or notification ac8nowledged within $ da!s of receipt

Initial e)aluation and consideration b* the MAAC within "", da!s of ac8nowledgement of application 'ee Note !# Applicant-s first response considered b* the MAAC within 1., da!s of receipt

Initial e)aluation completed within .$ da!s of ac8nowledgement of application 'ee Note %# Applicant-s first response e)aluated within '$ da!s of receipt

Initial e)aluation completed within 3$ da!s of ac8nowledgement of application

Initial e)aluation completed within 21 da!s of ac8nowledgement of application

4&aluation o+ additional data

Applicants- first response e)aluated within 21 da!s of receipt

Applicant-s first response e)aluated within 1' da!s of receipt

=ngoing re;uests for additional information and e)aluation of responses+ if applicable (a>ettal o+ consent Consent notice published in Ga)ette within 1$ da!s of sponsor being notified of Ministr*-s decision to recommend consent Consent notice published in Ga)ette within 1$ da!s of sponsor being notified of Ministr*-s decision to recommend consent 'ee Note :# 11, da!s appro(. 4 months# Consent notice published in Ga)ette within 1$ da!s of sponsor being notified of Ministr*-s decision to recommend consent 'ee Note %# $$ da!s appro(. % months# N.A

Total ti%e application under -edsa+e action Ce cluding the e!aluation of additional data <

"', da!s appro(. !9 months#

2' da!s appro(. ! month#

Notes: !. Bast3trac8ed new higher3ris8 medicine applications are normall* considered b* the MAAC within !%23!62 da*s of the decision to grant priorit*. %. Bast3trac8ed new intermediate3ris8 medicine applications are normall* e)aluated within :2 da*s of the decision to grant priorit*. :. The Ministr*-s decision to recommend appro)al is normall* made within : da*s of completion of the e)aluation report and peer re)iew process.

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80;
80;01

6rotection of (onfidential 'u))orting &nformation


6eriod of )rotection

The Medicines Amendment Act !""4 pro)ides a period of protection for confidential supporting information supplied with an application for consent to distribute a medicine containing a new acti)e substance. The pro)isions are designed to protect data from Kunfair commercial useL or disclosure. The re;uirement to protect confidential supporting information applies onl* to data submitted with an NMA. It does not appl* to data submitted subse;uentl* e.g. to support new indications for appro)ed products#. KConfidential informationL includes trade secrets and information that has commercial )alue that would be+ or would li8el* be+ diminished b* disclosure. KConfidential supporting informationL means confidential information contained in+ or relating to+ an application for consent to distribute an inno)ati)e medicine+ or confidential information about that medicine. As applications for multi3source medicines do not usuall* contain clinical or to(icological data+ reference ma* be made to data supplied b* the inno)ator to pro)e safet* and efficac*. As a result of the Medicines Amendment Act !""4 No. !%6+ data relating to an inno)ati)e medicine containing a new acti)e substance should not be used in the e)aluation of a multi3source product within the protected period 3 usuall* 9 *ears from the date of consent or the date of the decision to decline the application for consent to distribute the inno)ator product. Data in applications that ha)e been withdrawn b* the applicant are protected for a period of 9 *ears from the date of receipt of the application. This procedure applies to all applications under section %2 and section %: of the Medicines Act recei)ed after ! Panuar* !""9. The Medicines Amendment Act !""4 also gi)es retrospecti)e protection to confidential information. <owe)er+ disclosure of such information ma* be made at an* stage if it is in the interests of public health and safet*+ e)en if such information could be subNect to Ounfair commercial use-.

80;0+

!isclosure of data

The Minister ma* disclose data during the fi)e *ear Kprotected periodL to the following& an ad)isor* or technical committee appointed under section 6 of the Medicines Act !"6! the Medicines Classification Committee the Medicines Re)iew Committee a Go)ernment department or statutor* bod*+ for the purposes of that Go)ernment department or statutor* bod*+ or an ad)isor+ for the purpose of the Minister obtaining ad)ice about the medicine to which the data relates. Data will onl* be disclosed to a Go)ernment department+ statutor* bod*+ or ad)isor where the Minister considers steps will be ta8en to 8eep the data confidential. Disclosure ma* also be made to the ?<=+ the Bood and Agricultural =rganisation+ a regulator* agenc* of a ?orld Trade =rganisation member or a person.organisation appro)ed b* regulation. The grounds for disclosure to these groups are not limited to the protection of health and safet*. This is not considered to contra)ene the GATT KTRIP'L agreement+ because these organisations are either not in)ol)ed in the regulation of medicines or+ where the* are in)ol)ed+ there are safeguards in place

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

against Ounfair commercial use- of the data. Asuall* onl* part of the data will be released+ and will be insufficient to support a New Medicine Application from another compan*. Medsafe can disclose data to other regulator* authorities on two grounds. Birstl*+ to protect health and safet* e.g. where a ;uestion of safet*+ ;ualit* or efficac* has arisen# in which case it is usual for onl* that specific part of the data to be released. 'econdl*+ data can be disclosed to facilitate appro)al of the same product b* another regulator* agenc*. This relates to the e(change of information under the P>R 'cheme or the MoA with Australia. In this case+ onl* the e)aluation report is released not the actual data#. The e)aluation report can onl* be used to appro)e the identical product in an o)erseas mar8et+ and not to appro)e multi3source )ersions of the product.

80;03

Relationshi) with the $fficial &nformation Act 1<;+

?hen responding to a re;uest made under the =fficial Information Act !"6% =IA# for release of information on an application or notification+ Medsafe must consider the re;uirements of both the =IA and the Medicines Amendment Act !""4. Data that ma* be used for commercial ad)antage e.g. details of formulations+ manufacturing processes+ assa* and other test procedures# are protected from release under the =IA.

30;05

Effect on the e.aluation )rocess

1efore a New Intermediate3ris8 Medicine Application for consent to mar8et a multi3source medicine is e)aluated+ a chec8 will be made to determine whether the Kprotected periodL for the inno)ator product is still in force. >)aluation of the multi3source medicine application can commence during the protected period+ but no reference can be made to the inno)ator data without the consent of the inno)ator compan* and consent to distribute the multi3source product cannot be granted until after the end of the protected period. ?hen this situation arises+ the e)aluator will notif* the applicant that the protected period is still in force+ and outline the conse;uences for the assessment and appro)al of the product. The applicant ma* then choose to submit the additional data re;uired to enable the e)aluation of the application to be completed without the need to refer to the inno)ator data. If the additional data are pro)ided+ the e)aluation can be completed and consent granted prior to e(piration of the protected period.

80<

(ertificate of 6harmaceutical 6roduct

Pharmaceutical companies re;uiring formal certification of Ministerial consent ha)ing been granted for distribution of a medicine in New ,ealand ma* re;uest a %ertificate of 1harmaceutical 1roduct suitable for submission to o)erseas regulator* authorities. This certificate meets the re;uirements of the ?<= Certification 'cheme on the Hualit* of Pharmaceutical Products Mo)ing in International Commerce. It is referred to as a KBree 'ales CertificateL in some Nurisdictions. A separate certificate is issued for each name+ dose form+ strength and fla)our of each product and each countr* for which the certificate is re;uired.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

Re;uests accompanied b* the appropriate fee should be addressed to& The 'upport =fficer+ >)aluation Team Medsafe P= 1o( 92!: ?>00INGT=N

801,

'hort 'u))ly and !iscontinued Medicines

?hen the distribution of a medicine is li8el* to be affected b* a problem of short suppl* or its distribution is to be discontinued either temporaril* or permanentl*# the sponsor should ad)ise Medsafe as soon as possible+ preferabl* well in ad)ance+ so that Medsafe can consider the li8el* clinical implications and ta8e an* action re;uired.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

'ection 9:

General Re?uirements for A))lications and Notifications

Section summary "his section outlines the general re uirements for a--lications for Ministerial consent to distri+ute new and changed medicines and related -roducts#

901

Eligi*ility

The Medicines legislation re;uires that a New Medicine or Related Product Application NMA or NRPA# or a Changed Medicine or Related Product Notification CMN or CRPN# is lodged b* or in the name of a manufacturer+ importer or proprietor resident in New ,ealand. The New ,ealand resident manufacturer+ importer or proprietor ma* be an indi)idual or a compan* and is designated the KsponsorL or Klicence holderL# for the product concerned. The sponsor is legall* responsible for all aspects of the product in New ,ealand+ including an* regulator* action relating to it. The sponsor is responsible to ensure the accurac* of an* information submitted to Medsafe in support of an* NMA+ NRPA+ CMN or CRPN. An o)erseas pharmaceutical compan* wishing to mar8et a medicine or related product in New ,ealand therefore needs to ha)e a New ,ealand3based subsidiar* or appoint a local indi)idual or compan* as New ,ealand agent to act for them in New ,ealand as sponsor for the product concerned. The New ,ealand subsidiar* or agent is the sponsor responsible for the product+ including an* suppl* of the product under section % of the Medicines Act and an* recall of the product from the mar8et. An NMA or NRPA or CMN or CRPN is submitted to Medsafe in the name of the sponsor. An o)erseas branch of the compan* or a local or o)erseas regulator* affairs consultant ma* act on the sponsor-s behalf and prepare the paperwor8 for an application and submit it to Medsafe. Bor administrati)e purposes+ the identit* of the KapplicantL depends upon the circumstances& !. Man* applications and notifications are prepared+ signed and forwarded to Medsafe b* an emplo*ee of the sponsor e.g. a regulator* affairs manager or associate#. In this case the applicant is the sponsor. %. 'ome applications and notifications are prepared and submitted on the sponsor-s behalf b* an independent regulator* affairs consultant who signs the documentation as if he or she was an emplo*ee of the sponsor. In this case the applicant is the sponsor. :. 'ome applications and notifications are prepared and submitted on the sponsor-s behalf b* a local or o)ersees consultant who signs the documentation+ not as an emplo*ee+ but in his or her own right as a contracted agent of the sponsor. In this case the consultant not the sponsor# is the applicant.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

4. 'ome applications and notifications are prepared and submitted on the sponsor-s behalf b* an o)erseas branch of the compan*. An emplo*ee of the o)ersees compan* signs the documentation and forwards it to Medsafe. In this case the o)ersees branch of the compan* is the applicant while the New ,ealand branch is the sponsor. ?here a local or o)erseas regulator* affairs consultant or an o)erseas branch of a compan* acts on behalf of the sponsor in submitting an NMA+ NRPA+ CMN or CRPN+ a letter or cop* of a pre)ious letter# from the sponsor confirming the consultant-s or o)ersees compan*-s authorit* to act on the sponsor-s behalf should be forwarded to Medsafe+ either with the application.notification or separatel*. All Medsafe correspondence relating to the application or notification will be sent to the applicant+ irrespecti)e of whether the applicant is also the sponsor+ unless the applicant specificall* re;uests otherwise. Point applications in which all or part of the data are shared+ ma* be made b* two or more sponsors. It should be clearl* indicated in the application that each sponsor supports the shared use of the data. This ma* be indicated b* the co)ering letter s# being signed b* all sponsors. The letter s# must identif* the person to whom ;uestions and other correspondence relating to the application should be addressed. 'uch Noint applications commonl* relate to one product to be distributed under two or more brand names. Bor administrati)e purposes+ each brand name is treated as a separate product. <owe)er+ the application fee is calculated as for one principal product attracting a full fee with each additional brand name attracting a smaller additional fee as if was for an Kadditional nameL of the principal product.

90+

anguage

The medicines legislation re;uires applications and supporting data to be written in >nglish. Documents in languages other than >nglish e.g. GMP certificates and manufacturer-s licences# ma* be included in the application dossier pro)ided the* are accompanied b* a notarised >nglish translation.

903

Format

The preferred format for NMAs and NRPAs is the IC< Common Technical Document CTD# or the older K>A formatL for applications submitted in the >uropean Anion. If an application dossier in IC< or >A format is a)ailable+ this should be submitted unchanged e5cept for Part IA Administrati)e Data# which should be presented using the form gi)en in Appendi( % or :. ?here an application dossier in IC< or >A format is not a)ailable+ Part IA should be submitted and the remainder of the data pac8age supporting the NMA should preferabl* be assembled as far as reasonabl* possible to coincide with the IC< or >A format. Regardless of the format+ a detailed Table of Contents must be pro)ided to assist e)aluators in their assessment.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

905

&ndi.idual 6atient !ata

Normall* indi)idual patient data from clinical trials need not be included in an application dossier e(cept in the case of bioe;ui)alence studies where the indi)idual plasma.serum concentrations and deri)ed pharmaco8inetic data are to be supplied#. <owe)er+ tabulated indi)idual patient data ma* be included in clinical trial documentation if the applicant considers it appropriate. 1efore an application is lodged+ applicants should ensure that indi)idual patient data case report forms# are a)ailable in a format acceptable for submission in the >A or A'A+ and indicate in the application that these data are a)ailable. Indi)idual patient data not alread* supplied ma* be re;uested during the e)aluation period. ?here not alread* presented in the Clinical >(pert Report+ o)erall numbers of clinical trial patients and treatment subgroups should be tabulated and submitted with Part I of the application.

908

(o.ering etter

All NMAs and NRPAs should be accompanied b* a co)ering letter. A co)ering letter is not re;uired for a CMN or CRPN unless the sponsor wishes to pro)ide information additional to that gi)en in the CMN or CRPN form. 'ection 4 of the rele)ant CMN or CRPN form must be completed in full with the currentl* appro)ed details and the proposed changes described+ whether or not a co)ering letter is included. Bor higher3ris8 medicines+ the co)ering letter should indicate whether there are an* significant differences in the product+ its indications+ or the data submitted in New ,ealand+ Australia and >urope. An e(planation for such differences should be gi)en.

909

'u*mitting an A))lication or Notification

The applicant must ensure that the application dossier is complete. Medsafe does not carr* out detailed chec8ing of dossiers for completeness upon receipt. The* are accepted in good faith and placed in the appropriate e)aluation ;ueue. There ma* be situations when some data e.g. final stabilit* data# ma* not be a)ailable until later. If this is the case+ the situation should be e(plained and Nustified in a co)ering letter and an estimate of when the information can be e(pected to arri)e at Medsafe should be gi)en. =nce an e)aluator commences the assessment of the application or notification and finds that the dossier is incomplete in critical information e.g. an accompan*ing DMB or e;ui)alent data+ appropriate bioe;ui)alence data+ or stabilit* data sufficient to support a reasonable shelf3life are missing# and no ade;uate e(planation for the omission or indication of when the information can be e(pected to be supplied has been pro)ided+ the application ma* be reNected at this point and the application fee ma* not be refunded. Applicants+ therefore+ are strongl* ad)ised to chec8 carefull* all applications and dossiers of supporting data for completeness before submitting material to Medsafe. All data+ including supplementar* data+ must be submitted on A4 si/ed paper and should be bound in sturd* ring3binders or other t*pes of binders from which pages can be remo)ed and replaced# that do not spill their contents when opened. >ach part of the application should contain a detailed Table of Contents. Applicants wishing to submit data in electronic form should discuss the re;uirements with the >)aluation Team 0eader.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

=ne cop* of all applications and supporting data should be submitted. Bor applications to be considered b* the MAAC+ additional copies of the dossier of supporting data will be re;uested b* the MAAC 'ecretar* when re;uired usuall* about % months before the MAAC meeting to which the application has been assigned#. Applications for appro)al of new or changed labels or data sheets must be accompanied b* the appropriate notification form+ chec8list and a signed declaration. 'ee 'ections !% and !: and Appendices 6 S !: for details#. 'end completed applications with supporting data and the appropriate fee# to the Manager+ Medsafe at the address gi)en in section !.%. ?hen an application is accompanied b* cartons of supporting information+ each carton should be labelled clearl* with the product name and contents including )olume numbers#. 1o(es containing )olumes of data must be sturd* enough to pro)ide ade;uate protection to their contents. The* should also not e(ceed the weight that can be comfortabl* lifted. The courier should be ad)ised not to deli)er the bo(es to the reception des8 on the !6 th floor of Grand Plimmer Tower. Instead+ the courier should contact reception to notif* their arri)al and arrange access to the loc8ed data storage area on a lower floor of the building. The fee che;ue should not be enclosed in one of the cartons of data. It should accompan* the co)ering letter and Part IA for an NMA or NRPA+ and accompan* the CMN or CRPN form for a change notification.

90:

")dating the !ata 6ac2age

?hile a product is being e)aluated+ applicants should notif* Medsafe of& an* reNections or withdrawals of applications in other countries an* serious ad)erse effects obser)ed for the first time+ or at a fre;uenc* which has become a concern. Applicants should consider withdrawing an application if+ during the e)aluation period+ significant new data become a)ailable that are contrar* to the use of the medicine. Applicants are encouraged to update stabilit* data for New <igher Ris8 Medicines during the e)aluation process pro)ided the additional data can be recei)ed b* Medsafe no less than % months before the product is due for consideration b* the MAAC. This will allow the data to be ta8en into account in determining the shelf3life at appro)al and so reduce the need for changes later.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

90;

')onsors4 Res)onsi*ility to Retain (o)ies of All !ocuments

'ponsors are e(pected to retain a cop* of all documentation submitted to Medsafe and all correspondence relating to NMAs+ NRPAs+ CMNs and CRPNs+ and data sheets. The* are also e(pected to retain copies of product specifications and certificates of anal*sis for each batch of their products distributed in New ,ealand. In the e)ent of a compan* merger or ta8eo)er+ regulator* files should be transferred to the new sponsor.

90<

#echnical Guidelines to *e Followed

The technical data re;uirements for applications for consent to distribute new and changed medicines in New ,ealand are closel* aligned with those currentl* appl*ing in the >uropean Anion. The >uropean re;uirements are published b* the >uropean Commission >C# as the Rules Go!erning Medicinal 1roducts in the /uro-ean <nion . $arious other documents ha)e been published as additions and amendments to these Rules b* the Committee for Proprietar* Medicinal Products CPMP# ?or8ing Parties as ONotes for Guidance-. Medsafe also recognises the technical guidelines published b* the Anited 'tates Bood and Drug Administration. These CPMP and BDA documents are listed on >M>A and BDA Internet web sites and ma* be downloaded from there see 'ubsections 7.".% and 7.".:#. The International Conference on <armonisation IC<# has also de)eloped tripartite guidelines for use b* regulator* authorities in the >A+ A'A and Papan. ?hen these reach the final stage of adoption b* the IC< the* are normall* adopted b* the >C+ A'A and Papan as additions to+ or replacements for+ their guidelines. =nce IC<+ CPMP or BDA guidelines are formall* adopted and come into force in the >A or the A'A the* are recognised b* Medsafe. Medsafe also recognises rele)ant guidelines published in the 1ritish+ >uropean and Anited 'tates Pharmacopoeia and+ where rele)ant+ the guidelines published b* the ?orld <ealth =rganisation and the Australian Therapeutic Goods Administration TGA#. ?hile there are different administrati)e procedures appl*ing in New ,ealand and Australia+ there is substantial harmonisation of the data re;uirements for e)idence of ;ualit*+ safet* and efficac* of medicines and the grounds on which consent for distribution is granted in the two countries. Conse;uentl*+ there are considerable similarities between the re;uirements of Medsafe and the Australian TGA. <owe)er+ there are Australian3specific re;uirements for some aspects of the ;ualit* control and stabilit* data that are not rele)ant to New ,ealand. New ,ealand has a cooler climate than Australia and+ conse;uentl*+ the same stabilit* data ma* support a longer shelf life for room temperature storage in New ,ealand T%9C# than in Australia T:2C#. It is recognised that+ in some circumstances+ a different approach from that described in a guideline ma* be appropriate. <owe)er+ where an applicant chooses to submit a data pac8age that does not meet the rele)ant guideline+ that decision should be e(plained and Nustified in the dossier submitted in support of the application. The following situations are possible grounds for departing from current guidelines&

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

scientific de)elopment circumstances uni;ue to the product in ;uestion adoption b* the compan* of an acceptable approach which had not pre)iousl* been considered b* Medsafe sufficient alternati)e studies ha)ing been conducted which satisf* the criteria of ;ualit*+ safet* and efficac*. In assessing the chemical+ pharmaceutical and biological data submitted with new medicine applications and changed medicine notifications+ Medsafe generall* follows the technical guidelines published b* the International Conference on <armonisation IC<#+ the >uropean Commission and its Committee for Proprietar* Medicinal Products CPMP#+ and the Anited 'tates Bood and Drug Administration BDA#+ as well as the technical guidance pro)ided b* the 1ritish+ >uropean+ and Anited 'tates Pharmacopoeia which Medsafe regards as essentiall* e;ui)alent and e;uall* acceptable standards#. ?here appropriate+ Medsafe also ta8es notice of guidelines published b* the ?orld <ealth =rganisation ?<=# and the Australian Therapeutic Goods Administration TGA#. Medsafe recognises these o)erseas guidelines from the dates on which the* come into force internationall*. Medsafe e(pects to(ico3pharmacological studies and clinical studies supplied in support of an* new medicine application or changed medicine application to ha)e been carried out in accordance with the internationall* accepted standards of Good 0aborator* Practice and Good Clinical Research Practice. ?here a product or ingredient is controlled according to a pharmacopoeial monograph+ the specifications are to be updated to reflect an* re)isions to the monograph concerned. ?here a pharmacopoeial monograph e(ists+ this is considered to be the minimum re;uirements for the product or substance. Guidelines and pharmacopoeia are constantl* e)ol)ing as a result of scientific de)elopments and harmonisation of the re;uirements of the maNor o)erseas regulator* authorities. Medsafe endea)ours to 8eep abreast of such de)elopments and 8eep its e)aluation policies in line with Kbest international practiceL. ?here an IC< guideline e(ists for a particular aspect of a medicine e.g. impurit* limits+ )alidation of anal*tical procedures+ stabilit*# and has been adopted b* the >uropean+ A' and Papanese regulator* authorities+ conformit* to this guideline is the normal re;uirement for applications submitted to Medsafe. Applicants should ensure that the data in their application dossiers compl* with these IC< guidelines. It is recognised+ howe)er+ that older medicines ma* ha)e been de)eloped before publication of the IC< guidelines. The data pac8ages for these products ma* not meet current IC< guidelines+ but do meet earlier CPMP or BDA guidelines. In this situation+ the a)ailable data should be submitted for e)aluation. The data will be acceptable if the* can be seen to be effecti)el* e;ui)alent+ although not identical+ to those which would meet the re;uirements of the IC< guidelines. ?here no IC< guideline e(ists for a particular aspect of a medicine+ data will normall* be acceptable if the* compl* with the re;uirements of the CPMP and.or BDA guidelines. These guidelines are generall* e;ui)alent in intent+ if not alwa*s in their details. The IC<+ CPMP and BDA guidelines are listed on and a)ailable for downloading and printing from these organisations- web sites see below#.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

90<01

&(7 guidelines

The IC< has de)eloped and published numerous guidelines relating to the ;ualit*+ safet* and efficac* of medicines. Copies of these guidelines ma* be obtained from& IC< 'ecretariat c.o IBPMA :2 rue de 't3Pean P=. 1o( " C<3!%!! Gene)a !6 'wit/erland Ba(& U4!3%%3:49 6%59 IC< guidelines ma* also be obtained in electronic form printable pdf format# )ia the Internet from the following address& http:==www.i+p%a.org=ich$.ht%l.

90<0+

(6M6 guidelines

The >uropean Commission >C# has issued )arious directi)es relating to medicinal products. The Commission-s CPMP and its )eterinar* e;ui)alent the CP$P# has applied these directi)es in de)eloping a set of rules which ha)e been published in series of )olumes entitled Rules Go!erning Medicinal 1roducts in the /uro-ean <nion# $olumes %1+ :A+ :1 and :C are applicable to New ,ealand as well. $olume ! details >uropean Anion pharmaceutical legislation and >C directi)es and+ therefore+ is generall* not rele)ant to applications submitted in New ,ealand. $olume % is in : parts A+ 1 and C# and details the procedures for mar8eting authorisation in the >uropean Anion $ol. %A#+ the presentation and content of application dossiers+ summaries of product characteristics and e(pert reports $ol. %1# and regulator* guidelines $ol. %C#. Medsafe prefers that application dossiers submitted in New ,ealand are in the >A format as described in $olume %1. $olume : is also in : parts A+ 1 and C# and contains technical guidelines relating to the )arious sections of the dossier+ namel*& Hualit* and 1iotechnolog* $ol. :A#+ 'afet*+ >n)ironment and Information $ol. :1#+ and >fficac* $ol. :C#. Numerous other specific guidelines ha)e been drafted or finalised b* the CPMP ?or8ing Parties and issued as separate ONotes for Guidance-. $olume 4 details the >C re;uirements for good manufacturing practices GMP# for medicinal products for human and )eterinar* use. $olumes 9+ 7+ 5 and 6 detail >uropean pharmaceutical legislation+ regulator* procedures and technical guidelines for )eterinar* medicinal products. $olume " details >uropean re;uirements for pharmaco)igilance of both human and )eterinar* medicinal product. Printed copies of the >uropean Commission-s Rules Go!erning Medicinal 1roducts in the /uro-ean <nion and the indi)idual ONotes for Guidance- ma* be obtained from&

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

=ffice for =fficial Publications of the >uropean Communities %+ rue Mercier 03%"69 0u(embourg Ba( U:9%346695: or U:9%34676!5 Printed copies of the Rules Go!erning Medicinal 1roducts in the /uro-ean <nion ma* also be obtained from& <unter Publications 96a Gipps 'treet Collingwood $ictoria :277 Australia Ba(& U7!3:3"4!"35!94 Alternati)el*+ the Rules ma* be downloaded in printable electronic form pdf format# from the Internet site& http:==dg3.eudra.org=#2=eudrale5=inde5.ht%. Indi)idual ONotes for Guidance- ma* be obtained in printable electronic form pdf format# from the following Internet site& http:==www.e%ea.eu.int. 90<03 F!A guidelines

The A' BDA has published numerous guidelines dealing with all aspects of medicines. Copies of BDA guidelines ma* be obtained from& =ffice of Training and Communications Di)ision of Communications Management Drug Information 1ranch Bood and Drug Administration 9722 Bishers 0ane Roc8)ille+ MD %2696 A'A Ba(& U!3:2!36%534955 Most BDA guidelines rele)ant to New ,ealand re;uirements ma* also be obtained in printable electronic form pdf format# from the following Internet address& http:==www.+da.go&=cder=guidance=inde5.ht%. BDA guidelines relating to biological and biotechnological products ma* be obtained from& http:==www.+da.go&=c1er=guidelines=ht%.

901,

6ro)rietary Names

The proposed proprietar* name for a new medicine or related product must be clear+ unambiguous+ not unacceptabl* similar to+ or li8el* to be confused in an* wa* in print+ handwriting or speech with+ another medicine or related product currentl* registered in New ,ealand+ and not misleading in an* wa* with regard to the nature+ composition+ purpose+ uses or effects of the product.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

9011

!escri)tion of !osage Form

The dosage form description for a product should be selected from the following list& Capsule+ combination Capsule+ li;uid filled Capsule+ li;uid filled+ nasal inhalation Capsule+ modified release Capsule+ powder filled Capsule+ powder filled+ nasal inhalation Capsule+ soft gelatin Cement+ bone Cement+ bone+ li;uid component Cement+ bone+ powder component Chewing gum Chocolate+ medicated Combination Condom with spermicide Cream+ topical Cream+ )aginal Cr*stals Diluent Dressing+ medicated Drops+ ear Drops+ ear.e*e Drops+ ear.e*e.nose Drops+ e*e+ powder and diluent Drops+ e*e+ solution Drops+ e*e+ suspension Drops+ nasal Drops+ oral >li(ir >mulsion+ oral >mulsion+ topical >nema >*e disc >*e strip+ impregnated Boam Gargle+ powder for Gargle+ solution Gargle+ tablet for Gas Gel+ ophthalmic Gel+ oral Gel+ oral topical Gel+ topical Gel+ )aginal Granules+ effer)escent Granules+ modified release Granules+ oral <erb+ dried Implant+ subcutaneous Implant+ urethral Infusion+ concentrate Infusion+ emulsion Infusion+ powder for Infusion+ solution Inhalation+ capsule+ li;uid filled Inhalation+ capsule+ powder filled Inhalation+ powder Inhalation+ solution Inhalation+ solution+ powder for Inhalation+ suspension Inhalation+ )olatile li;uid Inhaler+ aerosol+ metered Inhaler+ aerosol+ non3metered InNection with diluent InNection+ concentrate InNection+ depot InNection+ emulsion InNection+ gel InNection+ granules for InNection+ powder for InNection+ solution InNection+ suspension Intrauterine contracepti)e de)ice Irrigation Irrigation+ e*e Irrigation+ powder for reconstitution. 0ac;uer+ nail 0inctus 0iniment 0otion+ scalp 0otion+ s8in 0o/enge Mouthwash+ solution =il =il+ bath =il+ topical =intment+ ear =intment+ ear.e*e =intment+ e*e =intment+ rectal =intment+ topical =intment+ )aginal

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

Pad+ s8in wash impregnated Paste+ oral Paste+ topical Pessar* Pill Powder Powder+ effer)escent Powder+ nasal Powder+ topical 'hampoo '8in wash 'oap 'olution 'olution+ antiseptic 'olution+ contact lens 'olution+ dial*sis 'olution+ dial*sis+ powder for 'olution+ intratracheal 'olution+ oral 'olution+ oral+ granules for 'olution+ oral+ powder for 'olution+ topical 'olution+ topical+ powder for 'olution+ )aginal douche 'ponge+ )aginal 'pra*+ contact lens solution 'pra*+ nasal solution 'pra*+ nasal suspension 'pra*+ oral 'pra*+ topical 'pra*+ topical powder 'tic8+ topical

'uppositor* 'uppositor*+ urethral 'uspension+ intratracheal 'uspension+ intratracheal+ powder for 'uspension+ oral 'uspension+ oral+ granules for 'uspension+ oral+ powder for 'uspension+ rectal.oral '*rup '*rup+ powder for Tablet Tablet for contact lens solution Tablet+ chewable Tablet+ chewable.dispersible Tablet+ coated Tablet+ dispersible Tablet+ effer)escent Tablet+ enteric coated Tablet+ film coated Tablet+ modified release Tablet+ soluble Tablet+ sublingual Tablet+ uncoated Tablet+ )aginal Test 8it Test 8it+ pregnanc* Test strip+ diagnostic Toothpaste Transdermal gel Transdermal patch $aginal ring ?afer

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

901+

Routes of Administration
Intraocular Intraperitoneal Intrapleural Intrasternal Intrauterine Intrathecal Intratracheal Intra)enous Intra)esical Nasal Not Applicable =ral =romucosal =tic Periarticular Perineural Rectal 'ubconNuncti)al 'ubcutaneous 'ublingual Transdermal Arethral $aginal

The description of the route of administration for a product should be selected from the following list& ConNuncti)al Cutaneous Dental >ndocer)ical >ndosinusial >pidural >(tra3amniotic Gingi)al <aemodial*sis Inhalation Insufflation Intra3amniotic Intra3arterial Intra3articular Intrabursal Intracardiac Intraca)ernous Intracer)ical Intracoronar* Intradermal Intradiscal Intralesional Intral*mphatic Intramuscular

9013

'helf ife and 'torage (onditions

The claimed shelf life must be supported b* stabilit* studies. 'uch studies should meet the re;uirements of the IC< guidelines for stabilit* testing. If specific storage conditions are re;uired+ the storage conditions statement should be selected or compounded using elements from the following list or words of similar meanings#& protect from light protect from moisture below 3%2VC Deep free/e# below 3!6VC Deep free/e# below 3!9VC Deep free/e# below 39VC Bree/e# at %V to 6VC Refrigerate+ do not free/e# at 6V to !9VC Cool# at !9V to %9VC Controlled room temperature# below %2VC Controlled room temperature# at or below %9VC below %9VC below :2VC

Note that in New ,ealand Kbelow %9VCL means room temperature+ whereas in Australia Kbelow %9VCL refers to air3conditioned facilities and Kbelow :2VCL refers to room temperature.

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'ection ::

&ngredients in Medicines and Related 6roducts

Section summary "his section -ro!ides details of the format and content of 7rug Master Files and %ertificates of *uita+ility 9t also details Medsafe re uirements for ensuring the freedom of acti!e ingredients and e>ci-ients from infecti!e agents and other harmful su+stances# Guidelines to read in conjunction with this section" CPMP& /uro-ean drug master file -rocedure for acti!e su+stances A/< Rules Vol# ':B BDA& Guideline for 7rug Mast er Files TGA& *u+ mi s si o n of 7ata for a 7rug Mast er File A7MFB on an :cti!e Raw Material, :--e n di > 0 in :ustralian Guideline s for the Registration of 7rugs, Volu m e 1, ?uly 1&& .# ?<=& Guidelines for assuring the uality of -harmaceutical -re-arations made +y recom+inant 7N: technology 8(,51(:RM52&#$.2 B*52&#160&

:01

!rug Master Files

Acti)e pharmaceutical ingredients APIs# are commonl* manufactured b* a compan* other than the manufacturer of the finished product. In such cases+ the manufacture+ ;ualit* control and stabilit* of the acti)e ingredient are usuall* described in a ODrug Master Bile- DMB#+ submitted to the regulator* authorit* b* the manufacturer of the acti)e ingredient. ?here the acti)e and finished product are manufactured b* the same compan*+ information on the production+ ;ualit* control and stabilit* of the acti)e substance ma* be submitted as part of the dossier for the finished product rather than in a separate DMB. In order to refer to the DMB in an application+ the applicant must ha)e the written permission of the acti)e ingredient manufacturer who submitted the DMB. A Kletter of accessL from the acti)e ingredient manufacturer+ addressed to Medsafe and indicating clearl* the applicant to which it applies must be sent to Medsafe b* the acti)e ingredient manufacturer+ either with the DMB or separatel*. If an acti)e substance manufacturer has supplied or been as8ed to suppl*# a DMB to Medsafe for the registration of a medicine+ it is not necessar* for a further cop* of the DMB or part thereof# to be pro)ided for the registration of another product sponsored b* a different sponsor. <owe)er+ the acti)e substance manufacturer needs to pro)ide Medsafe with a new letter of access+ referring to the pre)iousl* supplied DMB and the new applicant. Binished product sponsors are responsible for the ;ualit* of their products and the raw materials used to manufacture them. Therefore+ applicants should pro)ide written assurance that there is a formal agreement between the acti)e raw material manufacturer and the sponsor which ensures that information will be communicated to the sponsor+ and to Medsafe+ before an* significant change is made to the method of manufacture or specifications of an acti)e raw material used in a product distributed in New ,ealand. Hualit* control of the bul8 acti)e ingredient is carried out b* both the manufacturer of the acti)e ingredient and b* the manufacturer of the finished product. Testing b* the manufacturer of the bul8 acti)e ingredient is usuall* described in a DMB. Good Manufacturing Practice re;uires the finished product manufacturer to re3test the acti)e ingredient-s identit*+ potenc* and purit* before use in the

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

manufacture of finished products. This testing is usuall* described in the application dossier for the finished product. DMBs should be updated periodicall* to reflect an* changes. The sponsor concerned should ensure that either the updated DMB together with a detailed list of changes made#+ or details of an* changes made+ are forwarded to Medsafe. The changes made need to be described in sufficient detail to enable Medsafe to determine if an* material changes ha)e been made to the characteristics+ manufacture or ;ualit* control of the substance concerned and what those changes are. ?here formal e)aluation of the changes is re;uired+ the sponsor will be re;uired to submit a CMN and pa* the appropriate fee.

:0101

When is a !MF not re?uiredC

A DMB is not re;uired for& an* acti)e substance that is controlled according to the rele)ant monograph in the >uropean Pharmacopoeia and for which a )alid recentl* issued# >uropean Pharmacopoeial Commission KCertificate of 'uitabilit*L is pro)ided see 'ection 5.% for details# an* acti)e substance predominantl* used in a lower3ris8 medicine e.g. paracetamol# or related product+ but if the substance is also used in a higher3 or intermediate ris8 medicine+ a DMB or >uropean Pharmacopoeial Certificate of 'uitabilit* ma* be re;uired to support an NMA or CMN relating to that product. common inorganic substances and simple organic compounds a)ailable commerciall* in high purit* from chemical suppl* houses+ e.g. sodium chloride+ magnesium h*dro(ide+ naturall* occurring organic acids and their salts such as ascorbic acid and sodium citrate#+ sugars such as de(trose+ mannitol#+ amino acids e)en though the* ma* be s*nthesised rather than being e(tracted and refined#. 'imple+ unrefined e(tracts from plant materials. Although a DMB is not re;uired for these acti)e ingredients+ e)idence needs to be submitted b* the finished product manufacturer that the substance is obtained from a reliable source and consistentl* complies with the applicable pharmacopoeial or non3pharmacopoeial specifications. An* non3 pharmacopoeial specifications need to be assessed to determine their appropriateness and ade;uac* to ensure the ;ualit* of the substance.

:010+

Format for a !MF

DMBs compiled using the >uropean or A' format are acceptable in New ,ealand. If a DMB has alread* been assessed and appro)ed b* an o)erseas regulator* authorit*+ and the e)aluation report is a)ailable to the manufacturer+ a cop* of the full report should be forwarded with the DMB. If the report is not a)ailable+ the manufacturer should state when and b* whom the DMB was assessed and appro)ed. The DMB ma*+ if re;uired+ be presented in two sections+ with the first open# section containing information accessible to the finished dose form manufacturer and the second closed# section containing information not accessible to the finished dose form manufacturer.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

:0+

(ertificate of 'uita*ility

?here an acti)e ingredient is described in the >uropean Pharmacopoeia+ the manufacturer ma* submit the DMB or e;ui)alent documentation# to the >uropean Pharmacopoeial Commission for assessment and issue of a OCertificate of 'uitabilit*- Co'#. This certificate confirms that the purit* of the substance+ as produced b* the manufacturer+ is suitabl* controlled b* the monograph in the >uropean Pharmacopoeia. This certificate ma* then be submitted in lieu of a DMB+ ob)iating the need for regulator* authorities to carr* out their own detailed assessment of the data. Bor details of the certifications scheme+ contact the secretariat of the >uropean Pharmacopoeial Commission. 'ome information is a)ailable on the internet site& http:==www.pheur.org. ?here a Co' is submitted in lieu of a DMB+ the sponsor must also pro)ide a written assurance that an* conditions attached to the Co' b* the >uropean Pharmacopoeial Commission+ as well as an* agreed additional tests and limits e.g. for pol*morphic form+ particle si/e distribution+ impurities+ etc.# are applied to each batch used in product intended for the New ,ealand mar8et. The >uropean Pharmacopoeial Commission also assesses and issues Certificates of 'uitabilit* for substances used as acti)e ingredients or e(cipients in pharmaceutical products confirming that the* compl* with >uropean Pharmacopoeial re;uirements for minimising the ris8 of transmission of animal spongiform encephalopathies. Medsafe accepts these certificates. ?here a Co' is submitted in lieu of a DMB+ the applicant for consent to distribute a medicine in New ,ealand must ensure that the Co' is submitted with the written permission of the manufacturer of the bul8 acti)e ingredient to be used in manufacture of the finished product for the New ,ealand mar8et. 'ubmission of the Co' as part of the dossier of data supporting a new medicine application or changed medicine notification implies+ but does not pro)e+ that there is a commercial agreement between the applicant and the acti)e ingredient manufacturer. This agreement between the parties must be confirmed to Medsafe b* means of a formal Kletter of accessL from the acti)e ingredient manufacturer+ addressed to Medsafe and clearl* indicating the applicant and+ where possible+ the products to which it applies. The letter of access should also confirm that the acti)e ingredient manufacturer will+ if re;uested+ suppl* direct to Medsafe data relating to the manufacture+ ;ualit* control and stabilit* of the substance concerned.

:03

&ngredients of 7uman or Animal $rigin

Guidelines to read in conjunction with this subsection: IC< Guidelines& *-ecificationsC "est 1rocedures and :cce-tance %riteria for Biotechnological5Biological 1roducts Juality of Biotechnological 1roductsC Viral *afety /!aluation of Biotechnology 1roducts 7eri!ed from %ell =ines of (uman or :nimal ,rigin Juality of Biotechnological 1roductsC 7eri!ation and %haracterisation of %ell *u+strates <sed for 1roduction of Biotechnological5Biological 1roducts CPMP Guidelines+ etc& Note for Guidance on Minimising the Ris3 of "ransmitting :nimal *-ongiform /nce-halo-athy :gents !ia Medicinal 1roducts A%1M15B81512'05&2B 1osition 1a-er on -roduction of "allow 7eri!ati!es for <se in 1harmaceuticals A%1M15116'5&0B Note for Guidance on 1lasma47eri!ed Medicinal 1roducts A%1M15B8526&5&$B 1osition 1a-er on 1lasma4deri!ed Medicinal 1roductsC :lt "esting A%1M15B815'2$5&&B Note for GuidanceC Virus Validation *tudiesC "he 7esign, %ontri+ution and 9nter-retation of *tudies Validating the 9nacti!ation and Remo!al of Viruses A%1M15B8152625&$B

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

"he 9ntroduction of Nucleic :cid :m-lification "echnology AN:"B for the 7etection of (e-atitis % Virus RN: in 1lasma 1ools A%1M15B815'&05&0B BDA Guidelines& Guidance %oncerning 7emonstration of %om-ara+ility of (uman Biological 1roducts, 9ncluding "hera-eutic Biotech47eri!ed 1roducts Guidance for 9ndustryC 7onor *creening for :nti+odies to ("=V499 Guidance for 9ndustryC For the *u+mission of %hemistry, Manufacturing and %ontrols 9nformation for a "hera-eutic Recom+inant 7N:47eri!ed 1roduct or a Monoclonal :nti+ody 1roduct for 9n Vi!o <se Guidance for 9ndustryC Re!ised 1recautionary Measures to Reduce the 1ossi+le Ris3 of "ransmission of %reut)feld4?aco+ 7isease A%?7B and New Variant %reut)feld4?aco+ 7isease An!%?7B +y Blood and Blood 1roducts New ,ealand Guidelines& Minimum *tandards for the %ollection, 1rocessing and Juality :ssurance of Blood and Medicines 7eri!ed from (uman Blood and 1lasma ANew Zealand, 1&&2 # If a product contains an ingredient acti)e or e(cipient+ e.g. magnesium or calcium stearate+ stearic acid+ gelatin# that is+ or potentiall* is+ of human or animal origin+ or comes into contact with material of human or animal origin during manufacture+ the source of the material or contact# must be declared in the NMA or CMN. If it is of animal origin+ e)idence must be pro)ided that the product is free from )iruses+ other micro3 organisms and transmissible spongiform encephalopath* T'># agents. The guidelines listed abo)e should be followed in preparing the documentation to pro)ide this e)idence. A >uropean Pharmacopoeial Commission Certificate of 'uitabilit* is acceptable as e)idence of freedom from T'> agents.

:05

(olouring Agents

Regulation 7 of the Medicines Regulations !"64 contains a list of acceptable colouring agents for use in medicines in New ,ealand. <owe)er+ other colouring agents will generall* be acceptable pro)ided the* are acceptable colourings for use in foods or medicines in the >A+ A'A or Australia.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

'ection ;:

New Medicine A))lications

Section Summary "his section outlines the format and data re uirements for a--lications for Ministerial consent to distri+ute new and changed medicines and related -roducts# Legislation to read in conjunction with this section" Medicine :ct 1&21 *ection 21C :--lications for MinisterEs consent *ection 2'C Minister may gi!e -ro!isional consent *ection 2.C 7istri+ution of changed medicines restricted

;01
;0101

Formats for New Medicine A))lications


Format for a new inno.ati.e medicine a))lication

A new medicine application for a new chemical entit* or new biological entit* is be presented in two sections+ i.e. the administrati)e information and the dossier of supporting data to establish the ;ualit*+ safet* and efficac* of the product. The ad%inistrati&e data consists of the following documents as applicable for the particular t*pe of product#& Co)ering letter and fee che;ue or e)idence of electronic pa*ment ha)ing been made# Completed NMA form s# see Appendi( %# Certificates of 'uitabilit* 'ee 'ection 5.%# GMP documentation see 'ection !!# 0abelling see 'ection !%# Information leaflet.Pac8age insert 'ee 'ection !%.!!# Data sheet see 'ection !:# Copies of o)erseas e)aluation report s#

An NMA form must be completed for all New Medicine Applications. A separate form should be completed for each name+ dose form+ strength and fla)our. Note: The NMA form in Appendi( % has been re)ised. Applications recei)ed b* Medsafe after ! Panuar* %22% must be made using the re)ised form. Applications made using pre)ious formats published in earlier editions of these Guidelines recei)ed after ! Panuar* %22% will not be accepted for processing and will be returned to the applicant.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

The accompan*ing dossier o+ supporting *ualit!9 sa+et! and e++icac! data includes the following as applicable for the t*pe of application#& 'ummaries IC< format dossier+ Module %# or >A format >(pert Reports Chemical+ Pharmaceutical and 1iological documentation including separate Drug Master Bile s# if applicable# Pre3clinical.To(icolog* documentation Clinical documentation The preferred format for the dossier of supporting data for NMAs and NRPAs is either& !. The KIC< formatL Common Technical Document CTD# Modules % =)er)iews and 'ummaries of the Hualit*+ Non3clinical and Clinical data#+ : Hualit*#+ 4 Non3clinical 'tud* Reports# and 9 Clinical 'tud* Reports# as detailed in the IC< Guideline Multidisci-linary "o-ic M.C "he %ommon "echnical 7ocument and in the >uropean Commission-s "he Rules Go!erning Medicinal 1roducts in the /uro-ean <nion# Volume2BC Notice to :--licants, 2001 edition + or %. The K>C formatL Parts IC e(pert reports#+ Part II Chemical+ Pharmaceutical and 1iological Documentation#+ Part III To(ico3pharmacological Documentation# and Part I$ Clinical Documentation# as detailed in the >uropean Commission-s Rules Go!erning Medicinal 1roducts in the /uro-ean <nion, Volume2BC Notice to :--licants, 1&&2 edition# Brom ! Pul* %22% the IC< format will be the preferred format for all newl* assembled application dossiers. <owe)er+ the >A format will still be acceptable in cases where the dossier has pre)iousl* been assembled and submitted in that format to a regulator* authorit* in >urope or Australia. Medsafe does not e(pect applicants to re3format such material to the IC< format. If an application dossier in >A format is a)ailable+ this should be submitted unchanged e5cept for KPart IAL Administrati)e Data# which must be replaced with the N, NMA form so that all information rele)ant to the N, application is presented and that specific to >C administrati)e re;uirements is omitted. The accompan*ing KPart I1L documents GMP documentation+ data sheet+ labelling+ etc# should be submitted as the* are or adapted to New ,ealand re;uirements+ as appropriate. ?here an application dossier in either KIC< formatL or K>C formatL is not a)ailable+ Parts IA and I1 should be submitted according to the New ,ealand formats and re;uirements and the remainder of the data pac8age supporting the NMA should preferabl* be assembled as far as reasonabl* possible to coincide with either the IC< format Modules % S 9# or the >A format Parts IC+ II+ III and I$#. A detailed Table of Contents must be pro)ided with an* dossier+ regardless of the format+ to assist e)aluators in their assessment.

;010+

Format for an a*ridged new medicine a))lication dossier

A new medicine application for an KIntermediate Ris8L medicine including multi3source medicines and new dose forms and strengths of inno)ati)e and multi3source medicines# or for a K0ower ris8L medicine or related product is be presented in two sections+ i.e. the administrati)e information and the dossier of supporting data purporting to establish the ;ualit* and+ if rele)ant+ the bioe;ui)alence of the product and the corresponding inno)ator product.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

The ad%inistrati&e data consists of the following documents as applicable for the particular t*pe of product#& Co)ering letter and fee che;ue or e)idence of electronic pa*ment ha)ing been made# Completed NMA form s# see Appendi( %# Certificates of 'uitabilit* 'ee 'ection 5.%# GMP documentation see 'ection !!# 0abelling see 'ection !%# Information leaflet.Pac8age insert 'ee 'ection !%.!!# Data sheet see 'ection !:# Copies of o)erseas e)aluation report s#

The co)ering letter should indicate if one or more acti)e ingredient manufacturers ha)e been commissioned to submit direct to Medsafe Drug Master Biles DMBs# or Plasma Master Biles PMBs# as part of the application pac8age An NMA form must be completed for all New Medicine and New Related Product Applications including those for additional names+ dose forms and strengths or fla)ours#. A separate form should be completed for each name+ dose form+ strength and fla)our. Note: The NMA form in Appendi( % has been re)ised. Applications recei)ed b* Medsafe after ! Panuar* %22% must be made using the re)ised form. Applications made using pre)ious formats published in earlier editions of these Guidelines recei)ed after ! Panuar* %22% will not be accepted for processing and will be returned to the applicant. The accompan*ing dossier o+ supporting data includes the following as applicable for the t*pe of application#& 'ummaries IC< format dossier+ Module %# or >(pert reports pre3%22% >A format dossier+ Part I1# if a)ailableF not re;uired for low ris8 medicines# Chemical+ Pharmaceutical and 1iological data including separate Drug or Plasma Master Bile s# if applicableF not re;uired for low ris8 medicines# 1ioa)ailabilit* or bioe;ui)alence data if applicableF not re;uired for low ris8 medicines# Pre3clinical.To(icolog* data+ e.g. for new e(cipients if applicable# Clinical data if applicableF not re;uired for low ris8 medicines# The preferred format for the dossier of supporting data for NMAs and NRPAs is either& !. The KIC< formatL Common Technical Document CTD# Module % =)er)iews and 'ummaries of the Hualit*+ Non3clinical and Clinical data# and Module : Hualit*# and+ if rele)ant+ Module 4 Non3clinical 'tud* Reports# and Module 9 Clinical 'tud* Reports# as detailed in the IC< Guideline Multidisci-linary "o-ic M.C "he %ommon "echnical 7ocument and in the >uropean Commission-s "he Rules Go!erning Medicinal 1roducts in the /uro-ean <nion# Volume2BC Notice to :--licants, 2001 edition+ or %. The K>C formatL Part IC e(pert reports# and Part II Chemical+ Pharmaceutical and 1iological Documentation# and+ if rele)ant+ Part III To(ico3pharmacological Documentation# and Part I$ Clinical Documentation# as detailed in the >uropean Commission-s Rules Go!erning Medicinal 1roducts in the /uro-ean <nion, Volume2BC Notice to :--licants, 1&&2 edition#

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

Brom ! Pul* %22% the IC< format will be the preferred format for all newl* assembled application dossiers. <owe)er+ the >A format will still be acceptable in cases where the dossier has pre)iousl* been assembled and submitted in that format to a regulator* authorit* in >urope or Australia. Medsafe does not e(pect applicants to re3format such material to the IC< format. If an application dossier in >A format is a)ailable+ this should be submitted unchanged e5cept for KPart IAL Administrati)e Data# which must be replaced with the N, NMA form so that all information rele)ant to the N, application is presented and that specific to >C administrati)e re;uirements is omitted. The accompan*ing KPart I1L documents GMP documentation+ data sheet+ labelling+ etc# should be submitted as the* are or adapted to New ,ealand re;uirements+ as appropriate. ?here an application dossier in either KIC< formatL or K>A formatL is not a)ailable+ Parts IA and I1 should be submitted according to the New ,ealand formats and re;uirements and the remainder of the data pac8age supporting the NMA or NRPA should preferabl* be assembled as far as reasonabl* possible to coincide with either the IC< format Modules % and :# or the >A format Parts IC and II#. A detailed Table of Contents must be pro)ided with an* dossier+ regardless of the format+ to assist e)aluators in their assessment.

;0103

&(7 and E" formats for a*ridged dossiers

&(7 Format The IC< Common Technical Document# format headings for Chemical+ Pharmaceutical and 1iological Documentation are presented below. :.! :.% :.%.' :.%.'.! :.%.'.!.! :.%.'.!.% :.%.'.!.: :.%.'.% :.%.'.%.! :.%.'.%.% :.%.'.%.: :.%.'.%.4 :.%.'.%.9 :.%.'.%.7 :.%.'.: :.%.'.:.! :.%.'.:.% :.%.'.4 :.%.'.4.! :.%.'.4.% :.%.'.4.: :.%.'.4.4 :.%.'.4.9 :.%.'.9 :.%.'.7 :.%.'.5 :.%.P :.%.P.! TA10> =B C=NT>NT' 1=DW =B DATA DRAG 'A1'TANC> General Information Nomenclature 'tructure General Properties Manufacture Manufacturer s# Description of manufacturing process and process controls Control of materials Controls of critical steps and intermediates Process )alidation and.or e)aluation Manufacturing process de)elopment Characterisation >lucidation of structure and other characteristics Impurities Control of drug substance 'pecification Anal*tical procedures $alidation of anal*tical procedures 1atch anal*ses Pustification of specification Reference standards or materials Container closure s*stem 'tabilit* DRAG PR=DACT Description and composition of the drug product

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

:.%.P.% :.%.P.: :.%.P.:.! :.%.P.:.% :.%.P.:.: :.%.P.:.4 :.%.P.:.9 :.%.P.4 :.%.P.4.! :.%.P.4.% :.%.P.4.: :.%.P.4.4 :.%.P.4.9 :.%.P.4.7 :.%.P.9 :.%.P.9.! :.%.P.9.% :.%.P.9.: :.%.P.9.4 :.%.P.9.9 :.%.P.9.7 :.%.P.7 :.%.P.5 :.%.P.6 :.%.A :.%.A.! :.%.A.% :.%.A.: :.%.R :.:

Pharmaceutical de)elopment Manufacture Manufacturer s# 1atch formula Description of manufacturing process and process controls Controls of critical steps and intermediates Process )alidation and . or e)aluation Control of e(cipients 'pecifications Anal*tical procedures $alidation of anal*tical procedures Pustification of specifications >(cipients of human or animal origin 333 No)el e(cipients Control of drug product 'pecification s# Anal*tical procedures $alidation of anal*tical procedures 1atch anal*ses Characterisation of impurities Pustification of specification s# Reference standards or materials Container closure s*stem 'tabilit* APP>NDIC>' Bacilities and e;uipment Ad)entitious agents safet* e)aluation No)el e(cipients R>GI=NA0 INB=RMATI=N 0IT>RATAR> R>B>R>NC>'

E" Format The >A format headings for Chemical+ Pharmaceutical and 1iological Documentation for abridged applications are presented below. PART II A& Composition and presentation of product !. Composition of the product %. Container :. Clinical trial formula e# if applicable# 4. De)elopment pharmaceutics PART II 1& Method of preparation !. Manufacturing formula+ including details of batch si/e %. Manufacturing process for finished product including in3process control# :. $alidation of the process where a non3standard method of manufacture is used or the method of preparation is critical for the product# PART II C& Control of starting materials !. Acti)e pharmaceutical ingredients %. =ther ingredients :. Pac8aging material immediate pac8aging# PART II D& Control tests on intermediate products

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

PART II >& Control tests on the finished product !. 'pecifications and routine tests %. 'cientific data PART II B& 'tabilit* PART II G& 1ioa)ailabilit* . 1ioe;ui)alence if applicable# PART II H& =ther information

;0+

!ata Re?uirements for New Medicine A))lications

The re;uirements for the data supporting a new medicine application depend upon the categor* of product in)ol)ed&& New <igher3ris8 Medicine NMA3<# New Intermediate3ris8 Medicine NMA3I# New 0ower3ris8 Medicine NMA30# an application for pro)isional consent to distribute a new medicine

Please note that an =TC medicine does not automaticall* fall into the 0ower3ris8 Medicine categor*. New Intermediate3ris8 and 0ower3ris8 medicines usuall* contain acti)e ingredients that are listed in a pharmacopoeia and claim indications for which there is sufficient supporti)e published literature. ?here this is not the case+ a New Intermediate3or new 0ower3ris8 Medicine Application ma* need to contain clinical documentation to support the proposed indications+ and also possibl* rele)ant to(icological and pharmacological documentation. ?hile an application for pro)isional consent need not contain the same detail of safet* and efficac* data as that re;uired for full consent+ all a)ailable information should be included+ along with an e(planation of the t*pe of data still being collected and when these data will be a)ailable. ?hen the product that is the subNect of an NMA is closel* related to an e(isting product+ such as a new strength+ the applicant is onl* re;uired to submit data rele)ant to the introduction of the new product. The application must specif* all differences between the new and e(isting products and pro)ide data to support the safet*+ ;ualit* and efficac* of the new product. A complete dossier duplicating data alread* supplied for an e(isting product is not re;uired. Different pharmaceutical forms and strengths or fla)ours of a medicine re;uire separate application forms+ but ma* be supported b* reference to the same dossier of information. ?here a medicine has been e)aluated and appro)ed in Australia+ >urope+ Canada or the A'A and the o)erseas e)aluation reports are a)ailable+ sponsors should pro)ide copies of those reports along with an indication as to whether the supporting data submitted o)erseas was identical or not to the data submitted with the New ,ealand application. Product De)elopment Pharmaceutics are not normall* re;uired for lower ris8 medicines. The* ma* be re;uired for unusual dose forms or formulations. ?here pharmacopoeial test methods are used to control a finished product+ sufficient )alidation data should be pro)ided to confirm that the test methods wor8 satisfactoril* for the product concerned.

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;03

'tandard Re?uirements for New Multi=source -Generic/ 6rescri)tion Medicines

Medsafe-s standard re;uirements for the data for new intermediate3ris8 medicines are as set out below. Dossiers are assessed for conformit* with these re;uirements. Note: A chec8list is pro)ided in Appendi( 4 to assist applicants in ensuring that all of the re;uired data are included in their application dossiers. Applicants are as8ed to complete this chec8list and include it with the application.

Administrati.e &nformation
The proposed proprietar* name for the product must be clear+ unambiguous+ not unacceptabl* similar to+ or li8el* to be confused in an* wa* in print+ handwriting or speech with+ another medicine currentl* registered in New ,ealand+ and not misleading in an* wa* with regard to the nature+ composition+ purpose+ uses or effects of the product. Good Manufacturing Practice GMP# certification or other e)idence of GMP compliance must be pro)ided for each finished product manufacturing and pac8ing site and the certification& a# relates to the product or product class# concerned+ b# must be issued b* authorities recognised b* Medsafe+ and c# will not ha)e e(pired or be more than 9 *ears old b* the time the product is li8el* to be appro)ed for distribution in New ,ealand. Appropriate e)idence of GMP in the form of a GMP certificate or a DMB# must be pro)ided or ha)e been pro)ided pre)iousl*# for each acti)e ingredient manufacturing site. The labelling must compl* with the N, Medicines Regulations and Guidelines 'ee 'ection !%#. =therwise+ the labelling must be re)ised or+ if the criteria set out in 'ection !%.4 are met+ a labelling e(emption ma* be re;uested. If applicable+ the labels must allow eas* discrimination between the different strengths of the product. The draft data sheet must compl* with the N, Medicines Regulations and Guidelines see, 'ection !:#. In the case of a multi3source medicine+ the data sheet must be consistent with that of the corresponding inno)ator product. If applicable+ an* pac8age insert.information leaflet supplied with the product must be consistent with the New ,ealand product details and the data sheet. If an* e(cipients in the product are unsuitable for particular patient populations+ appropriate information or warnings must be included on the label or+ when space on the label does not permit+ in an information leaflet. pac8age insert# and also in the data sheet.

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(hemical> 6harmaceutical and Fiological !ocumentation


!omposition The dose form and formulation must be ade;uatel* Nustified+ appropriate for the medicine concerned and all of the ingredients are acceptable for use in human medicines. The ingredients must be compatible with each other. Dose deli)er* must be consistent within clinicall* acceptable limits. If rele)ant+ an* antio(idants and an* chemical or anti3microbial preser)ati)es included in the product must be ade;uatel* Nustified and their effecti)eness must be established. Ade;uate measures must be ta8en to ensure that an* animal3deri)ed ingredients e.g. gelatin+ magnesium or calcium stearate+ stearic acid# used in the product are free from T'> contamination. Different strengths of the product must be readil* distinguished e.g. b* differences in si/e+ colour+ shape+ mar8ings+ etc#. If tablets are scored+ e)idence that the tablets split e)enl* must be pro)ided. The primar* immediate# and secondar* outer# pac8aging and pac8aging materials+ closures+ induction or tamper3proof seals+ pac8 si/es+ an* dosing de)ice+ and an* desiccant or cotton wool contained in the pac8age must be appropriate for the product. If the N, Medicines Regulations re;uire the product to be in a safet* container+ it must be so pac8aged. "anufacture of #ctive $ngredient%s& Anless pre)iousl* submitted and appro)ed+ a satisfactor* Drug Master Bile s# or e;ui)alent information about the manufacture of the acti)e ingredient s# from each supplier of bul8 acti)e ingredient must be submitted. The DMB must describe in detail& the Kroute of s*nthesisL+ each step in the manufacturing and purification process+ the reaction conditions and in process controls for each step+ the ;ualit* control of starting materials+ reagents+ catal*sts+ sol)ents and an* isolated intermediates+ as well as an* subse;uent processing e.g. milling# of the bul8 substance. The DMB must also pro)ide proof of chemical and stereochemical structure of the substance and of an* significant impurities# using appropriate ph*sical+ chemical and spectroscopic methods. ?here rele)ant+ ade;uate e)idence of the cr*stalline form produced and control thereof must be pro)ided. "anufacture of 'inished Product The manufacturing+ sterilisation if an*# and pac8aging processes+ the e;uipment used+ and batch si/es must be described in detail+ appropriate and Nustified. An* o)erages or ranges of ;uantities for the acti)e ingredient s# or an* e(cipients must be appropriate and ade;uatel* Nustified. If rele)ant+ an* sterilisation processes must be Nustified+ and it must be established that harmful b*3 products are not formed during the sterilisation process. An* o)erfill of the container s# must be Nustified. An* sol)ents or gases used in the manufacturing process must be of ade;uate ;ualit*. If alternati)e processes are intended at some steps in the manufacture+ these ha)e been Nustified and shown to *ield finished product of e;ui)alent ;ualit*. The in3process controls incl. temperatures+ mi(ing times and speeds+ filter integrit*#+ test methods and acceptance limits at each step in the manufacturing+ sterilisation if an*# and pac8aging processes must be defined+ appropriate and ade;uate to assure batch ;ualit* and unit3to3unit consistenc*.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

If rele)ant+ an* processing e.g. neutralising+ cleaning+ washing+ sterilisation# of the containers before filling must be ade;uatel* controlled. If rele)ant+ controls on sterilit* of the e;uipment+ product and containers must be ade;uate throughout the process. If sterilisation is b* filtration+ the bioburden of the product before filtration must be ade;uatel* controlled+ the filter membrane pore si/e must be not more than 2.%% microns+ and the integrit* of the filter must be chec8ed before and after use. If sterilisation is b* autocla)ing or gamma irradiation+ the e;uipment and procedures must be described in detail and ade;uatel* controlled. If sterilisation of the product or container is b* treatment with eth*lene o(ide+ its use must be the onl* )iable option and the residue le)el must be controlled to not more than ! ppm in the product or ! mcg.ml container )olume+ and an* chloroh*drin residue must be controlled to not more than 92 ppm in the product or 92 mcg.ml container )olume. All critical steps in the manufacturing process including an* cleaning and.or sterilisation steps# must ha)e been ade;uatel* de)eloped and )alidated at each manufacturing site at either production scale or at pilot scale !2@ of full scale or !22+222 solid dose units+ whiche)er is the greater unless otherwise Nustified# using production scale e;uipment. If onl* pilot scale )alidation has been completed+ confirmation that full scale )alidation is scheduled for when commercial scale production commences must be pro)ided. (uality !ontrol of #ctive $ngredient%s& Ca< Controls applied 1! %anu+acturer o+ 1ul6 acti&e ingredient Anless pre)iousl* submitted and appro)ed+ a satisfactor* Drug Master Bile or a Ph >ur Commission KCertificate of 'uitabilit*L# from each supplier of bul8 acti)e ingredient must be submitted. The acti)e ingredient specifications applied b* the manufacturer of the bul8 acti)e ingredient must be in accordance with a recognised pharmacopoeia e.g. Ph >ur+ 1P+ A'P# or+ if non3 pharmacopoeial specifications are applied+ these must co)er all of the rele)ant identit*+ organoleptic+ ph*sical including cr*stalline form and particle si/e distribution+ if applicable#+ chemical+ stereochemical and microbiological ;ualit* parameters. Pustification must be gi)en for the selection of an* non3pharmacopoeial tests+ test procedures+ re;uirements and limits. If certain tests are not carried out routinel*+ ade;uate Nustification must be pro)ided. Ph*sical+ chemical and microbiological test procedures whether pharmacopoeial or not# must be self3)alidating or ha)e been )alidated in accordance with pharmacopoeial standards or IC< guidelines. All assa* and related product.degradation product and residual sol)ent impurit* le)el tests must ha)e been )alidated as appropriate# for specificit*.selecti)it*+ limit of detection+ limit of ;uantitation+ accurac*+ precision+ repeatabilit*+ linearit*+ stabilit* of solutions+ and robustness. ruggedness. Proof must be pro)ided that the related substance assa* procedure is ade;uate to detect and control all of the related substance impurities actuall* or potentiall* present in the bul8 substance produced using the intended manufacturing process. 'atisfactor* representati)e batch anal*tical data must be supplied for t*pical batches of bul8 acti)e substance. An* certificates of anal*sis submitted must ha)e been signed. If a KhouseL reference standard is used in the assa*s+ characterisation and anal*tical data confirming its suitabilit* for use must be pro)ided. C1< Controls applied 1! %anu+acturer o+ +inished product

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

The acti)e ingredient specifications applied b* the finished product manufacturer in testing bul8 acti)e substance before use in manufacture of the finished product must be in accordance with a recognised pharmacopoeia e.g. Ph >ur+ 1P+ A'P# or+ if non3pharmacopoeial specifications are applied+ these must co)er all of the rele)ant identit*+ organoleptic+ ph*sical including particle si/e distribution+ if applicable#+ chemical+ stereochemical and microbiological ;ualit* parameters. Pustification must be gi)en for the selection of an* non3pharmacopoeial tests+ test procedures+ re;uirements and limits. If certain tests are not carried out routinel*+ ade;uate Nustification must be pro)ided. Ph*sical+ chemical and microbiological test procedures whether pharmacopoeial or not# must be self3)alidating or ha)e been )alidated in accordance with pharmacopoeial standards or IC< guidelines in the testing laborator* ies# used b* the finished product manufacturer for routine ;ualit* control of the bul8 acti)e s#. All assa* and related product.degradation product and residual sol)ent impurit* le)el tests must ha)e been )alidated as appropriate# for specificit*.selecti)it*+ limit of detection+ limit of ;uantitation+ accurac*+ precision+ repeatabilit*+ linearit*+ stabilit* of solutions+ and robustness. ruggedness. 'atisfactor* representati)e batch anal*tical data generated b* the finished product manufacturer s# must ha)e been supplied for t*pical batches of bul8 acti)e substance from each supplier. An* certificates of anal*sis submitted must ha)e been signed. If a KhouseL reference standard is used in the assa*s+ characterisation and anal*tical data confirming its suitabilit* for use must be pro)ided. (uality !ontrol of E)cipient%s& The identit* and ;ualit* of all e(cipients including capsule shells and their constituents+ and an* gases used in filling )ials or ampoules# must be controlled b* either pharmacopoeial or appropriate in house specifications. An* non3pharmacopoeial specifications must be appropriate and ade;uatel* control identit*+ and ph*sical+ chemical and microbiological ;ualit* of the material. Ade;uate measures must be ta8en to ensure that an* ingredients of animal origin e.g. gelatin+ magnesium or calcium stearate+ stearic acid# used in the product are free from T'> contamination in accordance with >C and A' guidelines. 'atisfactor* representati)e batch anal*tical data must be pro)ided for an* e(cipients controlled b* non3pharmacopoeial specifications. An* certificates of anal*sis submitted must ha)e been signed. (uality !ontrol of Packaging "aterials %$mmediate Packaging& The pac8aging materials used pol*mers+ t*pes of glass+ etc.#+ containers+ seals+ closures and an* deli)er* de)ice s# supplied with the product must be clearl* defined+ suitable for pharmaceutical use+ and ade;uatel* controlled for identit*+ dimensions+ ph*sical and chemical properties+ manufacturing defects+ and sterilit*+ as applicable. An* plastic or rubber pac8aging.closure materials in contact with the product must be free from an* leachable to(ic impurities and must compl* with Ph >ur and A'P re;uirements for pol*meric materials used in pac8aging of medicines.

'atisfactor* representati)e batch anal*tical data must be pro)ided for an* primar* pac8aging materials+ containers and closures in contact with the product. An* certificates of anal*sis submitted must ha)e been signed.
(uality !ontrol of *elivery *evice%s&

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

An* deli)er* de)ice s# supplied with the product must be clearl* defined+ suitable for pharmaceutical use and ade;uatel* controlled for identit*+ dimensions+ ph*sical and chemical properties+ manufacturing defects+ sterilit*+ and dose deli)er*+ as applicable. (uality !ontrol of $ntermediate Products If there is an intermediate product+ it must controlled b* separate+ appropriate specifications that ade;uatel* control all rele)ant parameters. 'atisfactor* representati)e batch anal*tical data must be pro)ided. An* certificates of anal*sis submitted must ha)e been signed. (uality !ontrol of the 'inished Product The complete identit* and ;ualit* of the finished product must be ade;uatel* controlled at release and throughout its shelf3life b* appropriate pharmacopoeial or in house specifications that co)er all of the necessar* organoleptic+ ph*sical+ dissolution+ chemical+ microbiological and dose deli)er* parameters rele)ant to the dose form It must be clear which re;uirements appl* at release and which appl* throughout the shelf3life. If applicable+ an* non3pharmacopoeial test procedures used as replacements for+ or in addition to+ the procedures in a pharmacopoeial monograph must be appropriate and ha)e been Nustified. If all specified tests are not carried out routinel*+ Nustification must be pro)ided. The test procedures used must be self3)alidating or ha)e been ade;uatel* )alidated in accordance with pharmacopoeial re;uirements or IC< guidelines at each of the testing sites intended for routine ;ualit* control of the product. All assa* and related product.degradation product and residual sol)ent impurit* le)el tests must ha)e been )alidated as appropriate# at each testing laborator* in)ol)ed in the ;ualit* control of the product for specificit*.selecti)it*+ limit of detection+ limit of ;uantitation+ accurac*+ precision+ linearit*+ repeatabilit*+ stabilit* of solutions+ and robustness. ruggedness. 'atisfactor* recent anal*tical reports must be pro)ided for the final mar8et formulation s# of the product manufactured at least at pilot scale at each of the proposed manufacturing sites. Results must be included for each specified test and all of the reported test results must compl* with the specifications. If not+ an ade;uate e(planation or Nustification must be pro)ided. An* certificates of anal*sis submitted must ha)e been signed. +ta,ility of the #ctive $ngredient%s& The stabilit* of the acti)e ingredient s# is normall* described in the associated DMB s#. The stabilit* data submitted must ha)e been produced in accordance with IC< guidelines and ade;uatel* establish that the bul8 acti)e substance pac8aged in the intended storage container and stored under the prescribed storage conditions will remain within specifications for the whole of the claimed shelf3life or retest period.

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+ta,ility of the 'inished product The stabilit* of the mar8et formulations of the finished product or formulations that ma* reasonabl* be e(pected to ha)e the same stabilit*# pac8aged as intended for mar8eting must ha)e been tested in accordance with IC< guidelines including the IC< re;uirements for the number and si/es of batches used# unless otherwise Nustified. Preferabl*+ more than one batch of acti)e substance should ha)e been used in the manufacture of the stabilit* batches. The stabilit* trial protocol+ pac8aging+ pac8aging orientation if rele)ant#+ storage conditions and test procedures must be described in detail. All of the stabilit*3indicating organoleptic+ ph*sical+ chemical and microbiological ;ualit* parameters rele)ant to the dose form and t*pe of pac8aging must ha)e been included in the testing schedule and ha)e been monitored using appropriate+ clearl* defined+ )alidated in the testing laborator* used for the stabilit* samples#+ stabilit*3indicating test procedures. An* changes in test procedures during the stabilit* trials must be Nustified and results correlated. At least !% months data for storage under the recommended storage conditions must be a)ailable and be submitted with the application unless otherwise Nustified#. The stabilit* data should be updated before submission. ?here)er rele)ant+ results should be e(pressed ;uantitati)el* rather than as KcompliesL or Kpasses testL. An* lac8 of mass balance between assa*s and degradation products must be e(plained or discussed. If rele)ant+ preser)ati)e le)els or effecti)eness must be monitored. The results and allowing for e(trapolation within reasonable limits# must ade;uatel* support the proposed shelf3life under the recommended storage conditions otherwise a shorter shelf3life ma* be granted until ade;uate stabilit* data can be pro)ided to support the proposed shelf3life#. If rele)ant+ the stabilit* of the product after first opening+ reconstitution or dilution as applicable# must ha)e been in)estigated and shown to be ade;uate for the intended use of the product. If rele)ant+ ade;uate storage instructions and time3limits for use of the product after first opening or reconstitution or dilution must be stated on the draft product label+ in an* pac8age insert+ and in the Data 'heet. Fioe?ui.alence If applicable+ the bioe;ui)alence or+ if more appropriate+ clinical e;ui)alence# of the product and that of the appropriate reference product mar8eted in New ,ealand or an acceptable alternati)e product# must ha)e been established in accordance with the detailed re;uirements set out in 'ections !4 3 !7. The batches of trial and reference medicine used in the stud* must ha)e been of acceptable ;ualit*. The batch es# of trial medicine s# used in the biostud* must ha)e been of ade;uate scale and trul* representati)e of the product intended for mar8eting with respect to& a# formulation+ b# cr*stalline form.pol*morph of acti)e ingredient+ and c# particle si/e distribution of the acti)e especiall* if T!@ soluble in water# Cor an* differences in an* of these parameters must be unli8el* to affect the product-s bioa)ailabilit*D. If the batch of reference product used in the stud* was obtained from outside New ,ealand+ ade;uate e)idence that its formulation was the same as that distributed in New ,ealand must be pro)ided. The results e.g. for Tma(+ Cma( and mean plasma.serum concentrations after dosage# obtained in the biostud* must be consistent with the published pharmaco8inetic properties of the medicine. The pharmaco8inetic data must ha)e been subNected to the correct statistical anal*ses as detailed in 'ection#!9.!2.

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'ection <: (hanged Medicine Notifications


Section summary "his section outlines the format and data re uirements for a--lications for Ministerial consent to distri+ute changed medicines# Legislation to read in conjunction with this section" Medicine :ct 1&21, *ection 2.C 7istri+ution of changed medicines restricted

<01

Format for (hanged Medicine and Related 6roduct Notifications

?hen submitting a CMN the rele)ant forms and fee schedules gi)en in Appendices 9 and 7 should be used. CMN Borm A should be used for t*pe I and t*pe II products while CMN Borm 1 should be used for T*pe III products. Notifications recei)ed b* Medsafe after ! Panuar* %22% must be made using the forms and fee schedule below. Notifications using pre)ious formats recei)ed after ! Panuar* %22% will not be accepted for processing and will be returned to the applicant. >ach CMN or CRPN in)ol)ing a material change must be accompanied b* a CMN or CRPN form and summar* sheet+ pro)iding administrati)e details and outlining the changes being notified. A separate sheet should be completed for each product and all sections must be completed. Applicants should submit one cop* of the form+ summar* sheet and an* supporting documentation and the appropriate fee. The fees applied depend upon the t*pe of product and the amount of e)aluation in)ol)ed. T!pe I: T!pe II: Lower7ris6 %edicines and related products Inter%ediate7ris6 or Aigher7ris6 %edicines other than 1iological or 1iotechnological products C1ut including anti1iotics and li6e su1stances deri&ed +ro% %icro7organis%s< 2iological9 or 1iotechnological products Ci.e. &accines9 seru%s and allergens9 %edicinal products deri&ed +ro% hu%an 1lood or plas%a9 i%%unological %edicinal products9 and products deri&ed +ro% 1iotechnolog!<

T!pe III:

If the same change s# has been appro)ed b* another regulator* authorit* in Australia+ >urope or North America and that authorit*-s e)aluation report is a)ailable+ a cop* should be included with the CMN. ?here an applicant applies for consent to distribute a new medicine or related product and notifies the Director3General of changes to a currentl* mar8eted product at the same time the documentation must be 8ept separate. It is not acceptable to combine a CMN or CRPN with an NMA or NRPA. Medsafe will not accept further changes to a CMN or CRPN after it has been submitted e(cept+ perhaps+ to indicate or clarif* changes conse;uential to the changes notified in the original CMN or

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

CRPN#. If further non3conse;uential# material changes are intended a new CMN or CRPN and fee are re;uired. Note that when Medsafe issues formal consent for a change to a medicine or related product+ onl* those changes specificall* identified and applied for in the CMN or CRPN form are co)ered b* the consent. Material changes included in an* accompan*ing documentation but not specificall* identified in the CMN or CRPN form and conse;uentl* not assessed as changes+ are not included in an* consent that ma* be granted for the CMN or CRPN. Conse;uential changes are grouped with some material changes for the purpose of fees calculations. <owe)er+ these changes must be identified separatel* and supported b* appropriate data or documentation+ if rele)ant. >ach change included in a CMN or CRPN is assessed separatel*. In some cases+ Medsafe ma* consider that onl* some of the proposed changes can be appro)ed. This ma* be because the supporting data submitted with the CMN or CRPN do not Nustif* the other changes proposed. In this situation+ if the sponsor is unable to suppl* acceptable data to support the proposed change s#+ a recommendation to withdraw those changes from the CMN or CRPN will be made to the sponsor. This will enable consent to be granted for the appro)able changes. Partial consent for some of the changes+ with other changes assessed later+ is not Medsafe-s current practice. An* proposed changes withdrawn from a CMN or CRPN can be resubmitted as a new CMN or CRPN at a future date when the re;uired supporting data are a)ailable. This new notification must be accompanied b* a new fee appl*ing to those particular changes

<0+

!ata Re?uirements for (hanged Medicine or Related 6roduct Notifications

The data re;uired to support a Changed Medicine Notification or Changed Related Product Notification is essentiall* the same as that re;uired for the corresponding section of a New Medicine Application . >(cept in the case of a changed label or data sheet+ no data are re;uired to be submitted with a 'elf3 assessable Change Notification. The applicant must+ howe)er+ hold the data re;uired to show that the change is acceptable and must be able to suppl* the data to Medsafe on re;uest. In the case of other changes+ the following data should be pro)ided+ and if not pro)ided+ ma* be re;uested b* the e)aluator& Formulation Certificates of Anal*sis issued b* the finished product manufacturer for % or : representati)e batches of an* new e(cipient if that e(cipient is not controlled in accordance with a recognised pharmacopoeial monograph. Comparati)e dissolution data for the proposed new and currentl* appro)ed finished products using a discriminator* test+ must be supplied for tablets and capsules. The data need to establish that there are no significant differences between the new and original formulations. Certificates of Anal*sis for the finished product manufactured using the proposed new formulation. At least one batch should be full production scale unless otherwise Nustified+ while the other batches should be at least pilot scale manufactured using full production scale e;uipment. 1ioe;ui)alence data if re;uired see note below# 'tabilit* data if re;uired see note below# If the formulation in)ol)es a change to the preser)ati)e s*stem+ then additional data ma* be re;uired such as& !. Proof of anti3microbial efficac* of the finished product at e(pir*.

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%. Test methods and )alidation data# for the determination of preser)ati)e content at finished product release. :. 'tabilit* data including microbial ;ualit*#. Note: The following changes are considered unli8el* to ha)e an impact on the stabilit* or bioa)ailabilit* of an immediate release or modified release solid oral dose form& !. %. Remo)al+ replacement or reduction in the amount of a colouring or fla)ouring agent. A change in the percentage content of an* of the following e(cipients pro)ided that& a. the change in the amount of an indi)idual e(cipient does not e(ceed the ma(imum allowable change for that e(cipient as shown in the table below+ and b. the total additi)e change to all non release3controlling e(cipients is not more than 9@ of the total formulation+ and c. the total additi)e change to all release3controlling e(cipients in a modified release dose form is not more than 9@ of the total formulation+ and d. the total weight of the dosage form is still within the pre)iousl* appro)ed range. 45cipient #iller 0isintegrant: 'tarch =ther 2inder Lu1ricant: Calcium stearate Magnesium stearate =ther (lidant: #il% coat Talc =ther -a5i%u% allowa1le change Cas percentage o+ total weight< 9@ :@ !@ 2.9@ 2.%9@ 2.%9@ !@ !@ 2.!@ !@

If a product undergoes a series of stepwise formulation changes+ bioa)ailabilit* data will be re;uired if the o)erall change e(ceeds the limits stated abo)e. ?hen an application is made for appro)al of a change to the formulation of a solid oral dose form+ and the change falls within the criteria abo)e+ a bioe;ui)alence stud* and stabilit* stud* are not re;uired to be submitted with the change notification. Bor an* formulation change that falls outside the criteria gi)en abo)e+ the applicant must either pro)ide stabilit* and bioa)ailabilit* data+ or pro)ide ade;uate Nustification for not doing so.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

'ite of manufacture -Acti.e ingredient/ >ither a Drug Master Bile with accompan*ing Kletter of accessL+ or a >uropean Pharmacopoeial Certificate of 'uitabilit* with accompan*ing Kletter of accessL+ or if the finished product is Klow ris8L# Certificates of Anal*sis for representati)e batches of acti)e ingredient issued b* the finished product manufacturer. 'ite of manufacture -Finished )roduct/0 GMP certification for the new site+ if a)ailable+ or other acceptable e)idence of GMP compliance at the site see 'ection !!#. Appropriate )alidation of the process at the new site must be submitted to demonstrate that product manufactured at this site meets the currentl* registered re;uirements for in process controls and the finished product specifications. Description and )alidation of ;ualit* control test methods where there is a change in test procedures or the laborator* testing the product. Certificates of Anal*sis for representati)e batches of finished product manufactured at the new site. At least one batch should be full production scale unless otherwise Nustified+ while other batches should be at least pilot scale manufactured using full production scale e;uipment. Comparati)e dissolution data using a discriminator* test+ must be supplied for tablets and capsules. The data need to establish that there are no significant differences between product made at the old and new sites. Rele)ant stabilit* data must be generated for batches produced at the new site as re;uired b* GMP. Medsafe ma* re;uest the Compan* to pro)ide accelerated stabilit* data for a particular medicine where stabilit* is 8nown to be a problem or where changes in stabilit* could ha)e clinical conse;uences. The rele)ant stabilit* data need not necessaril* be supplied prior to the issue of a consent for the change of site. <owe)er+ if stabilit* data are not supplied+ the Compan* must pro)ide written assurance that stabilit* data will be generated and Medsafe notified immediatel* if there are an* significant problems identified or if the data indicate that the stabilit* of product from the new site is different from that made at the original site to the e(tent that the shelf life of the medicine would be affected. If the application complies with the BDA-s Guidance for Industr* on 'cale3Ap and Post3Appro)al Changes 'APAC# re;uirements+ this is also acceptable. Manufacturing )rocess -Acti.e ingredient/0 Description of changed manufacturing process and in3process controls. Certificates of Anal*sis for representati)e batches of acti)e ingredient manufactured using the new process. Manufacturing )rocess -Finished )roduct/0 Description of the changed manufacturing process including )alidation and in3process controls. Certificates of Anal*sis for representati)e batches of finished product manufactured using the proposed process. At least one batch should be full production scale unless otherwise Nustified+ while the other batches should be at least pilot scale manufactured using full production scale e;uipment. Comparati)e dissolution data for representati)e batches of the finished product using a discriminator* test+ must be supplied for tablets and capsules. The data need to establish that there are no significant differences between product manufactured using the new and original manufacturing processes. 'tabilit* data or confirmation that stabilit* data will be collected. Rele)ant stabilit* data must be generated for batches produced using the new process as re;uired b* GMP. Medsafe ma* re;uest the Compan* to pro)ide accelerated stabilit* data for a particular medicine where stabilit* is 8nown to be a problem or where changes in stabilit* could ha)e clinical conse;uences. The rele)ant stabilit* data need not necessaril* be supplied prior to the issue of a consent for the change of process. <owe)er+ if the data are not supplied+ the Compan* must pro)ide written assurance that stabilit* data will be generated and Medsafe notified immediatel* if there are an* significant problems identified or if the data indicate that the stabilit* of product from the new process is

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

different from that made at the original process to the e(tent that the shelf life of the medicine would be affected. 1ioe;ui)alence data if re;uired. ')ecificationsDtest methods -acti.e ingredient and finished )roduct/ Pustification for specification changes. $alidation of an* changed test methods. Certificates of Anal*sis for the acti)e ingredient or finished product demonstrating the abilit* of the compan* to meet specifications. 6ac2aging Pac8aging materials specifications. 'tabilit* data if the pac8aging ma* be e(pected to be less protecti)e than the currentl* appro)ed pac8aging. New and e1tended indications Pustification or supporting clinical data as appropriate# and a draft re)ised data sheet.

<03

'elf=assessa*le (hanges

=ne cop* of the CMN or CRPN form should be submitted+ along with the appropriate fee+ for a material change that is self3assessable. Medsafe ac6nowledges but does not formall* Kappro)eL or issue a Kconsent noticeL for self3assessable change notifications. 'ACNs are subNect to audit and then+ if a 'ACN is found to be unsatisfactor*+ Medsafe ad)ises the sponsor and re;uests rectification of the unsatisfactor* or inappropriate aspect s# of the 'ACN e.g. b* submission of a formal CMN#. =nce the CMN is e)aluated and found to be satisfactor*+ a consent notice is issued for that CMN.

a*els and data sheets


?hen a self3assessable change is made to a label or data sheet+ the appropriate chec8list and declaration must be completed b* the applicant and submitted with the CMN or CRPN form+ along with copies of the pre)iousl* appro)ed and new labels or data sheets. 'ee 'ections !% and !: for further details. A CMN or CRPN is not re;uired when the onl* change to a label is the classification statement as long as no other changes to the label are re;uired as a conse;uence of reclassification#. In this case all that is re;uired is a cop* of the new label for inclusion in Medsafe-s product file.

(hange of s)onsor
?hen a change in sponsor for a product s# is to be made+ a self assessable CMN or CRPN is re;uired pro)iding details of the change and all of the products in)ol)ed. 0etters or other documentar* e)idence from both the new and old sponsor or the manufacturer+ if that is more appropriate# confirming the arrangement should be submitted with the CMN or CRPN.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

<05
<0501

(hanges Not Re?uiring a (MN or (R6N


(hanges in 6harmaco)oeial ')ecifications

A CMN or CRPN is not re;uired for updating of specifications for an acti)e ingredient+ e(cipient or finished product to conform to the most recent edition of the rele)ant pharmacopoeial monograph. Manufacturers are e(pected to 8eep their specifications in line with an* re)isions to those monographs. <owe)er+ a CMN or CRPN is re;uired if there is a change from the specifications of a monograph in one pharmacopoeia to that in another pharmacopoeia+ or from in house specifications to a pharmacopoeial monograph or !ice !ersa#.

<050+

(hanges in names of manufacturers or )ac2ers

?hen the name of a manufacturer or pac8er is changed but there are no changes to the address or the manufacture or pac8ing processes a CMN or CRPN is not re;uired. Instead+ the sponsor should ad)ise Medsafe b* letter so that Medsafe can update its records.

<0503

")dates to !rug Master Files

DMBs should be updated periodicall* to reflect an* changes. 'ponsors should ensure that such updated DMBs together with a list of changes made#+ or at least# details of an* changes made+ are forwarded to Medsafe. Medsafe considers the list of changes made and+ if the changes are such that formal e)aluation of them is re;uired+ the sponsor will be re;uired to submit a formal CMN and pa* the appropriate fee.

<0505

")dates to 6lasma Master Files

Plasma master files should be updated annuall* to reflect an* changes in the disease epidemiolog* of the donor group. The sponsor is re;uired to forward a cop* of the re)ised data to Medsafe which then considers the changes and+ if action is re;uired+ ad)ises the sponsor accordingl*.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

'ection 1,:

New and (hanged Related 6roducts

Section summary "his section outlines the format and data re uirements for a--lications for Ministerial consent to distri+ute new and changed related -roducts# Legislation to read in conjunction with this section" Medicine :ct 1&21, 1art V99 Asections &.4&6C Related 1roducts

1,01

!ata Re?uirements for New Related 6roduct A))lications

An application for consent to distribute a new related product should be accompanied b* the following data& A0 Related )roducts other than dentifrices $ +ummary of the *ossier Administrati)e data+ including purpose and directions for use 0abelling+ accompanied b* a self3assessment chec8list and declaration CNote that GM1 certification need not +e -ro!ided for related -roducts# D

$$ !hemical- Pharmaceutical . /iological *ocumentation Composition and presentation of product Note& Product De)elopment Pharmaceutics are not re;uired.# Method of preparation 'pecifications for acti)e ingredients Control tests on e(cipients need not be supplied.# 'pecifications for the finished product $alidation data should be pro)ided to confirm that the proposed test methods wor8 satisfactoril* for the characteristics that establish the therapeutic nature of the product concerned.# 'tabilit* Re;uired onl* for products ta8en internall*+ or otherwise+ if rele)ant.# =ther information if rele)ant# F0 !entifrices Dentifrices can be either related products or medicines. The two factors that determine whether a dentifrice will be assessed as a related product or a medicine are !# the fluoride content+ or %# the e(tent of the claims made for the product. An* dentifrice containing more than 2.!@ !222 ppm# of elemental fluoride will be regarded as a medicine. An* mouthwash formulated so that it can be swallowed to supplement fluoride inta8e will be regarded as a medicine.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

Bor dentifrices that are related products+ sponsors should submit and assessment will be restricted to# the following information& Administrati)e data as re;uired in 'ection ! of the NRPA form# 0abels Therapeutic claims Therapeutic efficac* of the acti)e ingredients if an acti)e ingredient other than fluoride is used# Hualit* control of the acti)e ingredient s# both as the raw material+ and in the finished dose form# and representati)e batch anal*tical data for the finished product.

Bormulation details ma* be supplied+ but will not be assessed in detail. An* future changes to formulations that are purel* cosmetic in nature and do not affect the acti)e ingredient s# will not re;uire the submission of a CRPN. <owe)er+ the sponsor is responsible to ensure that compliance with regulator* re;uirements relating to colours+ fla)ours+ etc is maintained. The following information need not be supplied for a dentifrice& GMP certification Product de)elopment Manufacturing method and in process control Hualit* control of the e(cipients or the finished product e(cept for controls on acti)e ingredient identit* and content# 'tabilit* data The following claims for therapeutic efficac* for dentifrices containing fluoride are acceptable an* other claims or words of similar meaning will re;uire assessment#& Gums& hel-s maintain healthy teeth and gums Pla;ue tartar+ calculus#& remo!es, reduces, -re!ents, fights, loosens, hel-s neutralise -la ue acids Tooth deca*& -rotects against, -re!ents, fights, com-lements +rushing, reduces ca!ities Teeth and tooth enamel& -rotects, toughens, hardens, strengthens, cleans, shines, -olishes, +rightens, whitens, maintains healthy teeth, remo!e stains Mouth& 3ee-s mouth and +reath fresh and clean, fights +ad +reath, hel-s relie!e dry mouth Bor Nunior formulations of fluoride toothpastes+ the following warning statements+ or words of similar meanings+ must be included on the labels& %hildren under the age of $ should use no more than a smear A$mmB of fluoride tooth-aste on a small +rush#Q %hildren should +e discouraged from swallowing or eating tooth-aste# Q B Note: Bor further details+ see 1rescri+er <-date No. !2+ =ctober !""9+ pages !:3!7. Copes of 1rescri+er <-date are a)ailable on re;uest from Medsafe.#

1,0+

!ata Re?uirements for (hanged Related 6roduct Notifications

The procedure and data re;uirements for changed related product notifications are similar to those for 0ower3ris8 medicines and should be submitted to Medsafe using the CRPN Borm in Appendi( 5.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

'ection 11:

Good Manufacturing 6ractice !ocumentation

Section summary "his section e>-lains when e!idence of com-liance with GM1 is re uired and what e!idence is acce-ta+le#

1101

When is GM6 !ocumentation Re?uiredC

Medsafe re;uires e)idence of Good Manufacturing Practice GMP# compliance for each finished product manufacturing site and pac8aging site specified in a New Medicine Application or Changed Medicine Notification. >)idence of GMP compliance is re;uired for products regarded as medicines in New ,ealand+ whether or not the* are considered medicines in the countr* of origin. Bor bone cement containing an antibiotic+ condoms containing a spermicide+ intrauterine contracepti)e de)ices containing copper+ and pregnanc* tests+ all of which are regarded as medical de)ices o)erseas but are medicines in New ,ealand+ e)idence of compliance with the rele)ant medical de)ice GMP re;uirements in the countr* of origin e.g. >urope+ A'A+ Australia# is re;uired. In the case of related products+ e)idence of compliance with GMP is re;uired for NRPAs and CRPNs for products ta8en internall* e.g. throat lo/enges+ and )itamin and mineral tablets#. >)idence of GMP is not re;uired for related products used e(ternall* such as fluoride toothpaste containing not more than 2.!@ elemental fluorine+ fluoride mouthwash and antidandruff shampoos categorised as related products. <owe)er+ Medsafe e(pects the manufacturer to compl* with a suitable GMP standard. Bor bul8 acti)e pharmaceutical ingredients e)idence that the material is manufactured consistentl* and produced with acceptable ;ualit* is re;uired. GMP certification+ or e;ui)alent documentar* e)idence+ stating the products or product classes for which it has been granted is re;uired for all& manufacturers of the finished product including manufacturers of intermediate products# sterilisers of the finished product pac8ers of the finished product sites where products are o)erlabelled

A manufacturing site for a finished product is an* site which contributes to a manufacturing operation which con)erts bul8 raw materials to a finished dose form. This includes sterilising sites. A pac8ing site means an* site which contributes to a pac8ing operation which places the final dose form into its labelled primar* or secondar* container. Manufacturers and.or pac8ers with premises in New ,ealand must hold an appropriate current licence to manufacture and.or pac8 medicines. The licence must ha)e been issued for the site for the manufacture and.or pac8aging of the t*pe of product or pac8aging operation before manufacture or

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

pac8aging of the product for distribution can commence. Pro)ided the* hold such current licences+ certification need not be pro)ided with each application or notification. Bor o)erseas manufacturers and pac8ers+ Medsafe re;uires that certification be included with each NMA or CMN which relates to a change of site+ e)en if the site alread* supplies product to New ,ealand and certification has been supplied pre)iousl* with an earlier application or notification. This reduces dela*s associated with locating other files+ and because it is desirable for the certification to be product3specific and up3to3date. Acceptable e)idence of GMP compliance normall* consists of copies of appropriate certificates+ manufacturing licences or reports issued b* a regulator* authorit* whose competence is recognised b* Medsafe. Details of the documentation that is acceptable and a list of authorities whose competence to certif* GMP compliance is recognised b* Medsafe are gi)en below in section !!.9. The certificate+ licence or report should be no more than : *ears old when the NMA or CMN is submitted+ and must be no more than 9 *ears old at the time of appro)al of the new or changed product for distribution in New ,ealand# If the original documentation was in a language other than >nglish then copies of both the original documents and a certified >nglish translation must be submitted. If acceptable e)idence of GMP compliance is not a)ailable+ an audit of the site b* Medsafe auditors can be arranged at the applicantXs re;uest and e(pense.

110+

Recognised !ocumentation

GMP certification recognised b* Medsafe can be an* document issued b* a recognised authorit* which attests to GMP compliance. 0egible photocopies of the documents are acceptable. Documents should contain the following information& the street address of the site concerned reference to the product or product class reference to GMP acceptabilit* and.or to a GMP audit name and address of the issuing authorit* date and signature. date of e(pir* of the certification or licence

The following are e(amples of acceptable e)idence of GMP certification& licence to manufacture issued b* a recognised authorit* where such a licence is issued onl* where the site is inspected and regularl* re3inspected for GMP compliance current registration and entr* for the product+ product class or process concerned# of the site in the Australian Register of 0icensed Manufacturers Anited Gingdom Product 0icence or Product 0icence $ariation where name and address of site is shown certification of pharmaceutical product issued under the ?<= scheme b* a recognised authorit* which certifies the ;ualit* of pharmaceuticals mo)ing in international commerce Canadian Drug Plant Inspection Rating Report a letter or file note from a recognised authorit* which attests to GMP compliance. The most usual e(ample seen is an e(tract from BDA files obtained b* the manufacturer under the A' Breedom of Information Act. It usuall* states that an audit occurred on the gi)en date and gi)es the outcome of the audit

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

a certificate issued b* the Australian TGA confirming that it has confirmed e.g. with the A' BDA# that GMP compliance at the particular site is satisfactor*. Note that Medsafe also has access to the BDA-s electronic GMP database and can chec8 the GMP status of manufacturing sites inspected b* the BDA. The following are N=T acceptable as e)idence of GMP compliance& a licence to manufacture which is not issued b* a recognised authorit* certification issued b* a pharmaceutical compan* 3 e)en if the compan* certif*ing is not the same as the manufacturer or pac8er Annual Registration of Drug >stablishment A'A#. This document is not indicati)e of GMP compliance.

1103

(lasses of Medicine

Certification should preferabl* be product3specific. Certification in the ?<= format or a manufacturing or product licence listing the product are the most easil* obtained e(amples of this t*pe. If product3specific certification cannot be obtained+ the certification must relate to a medicine or medicines of the same class es# see below# as the one which is the subNect of the application or notification. A medicine ma* belong to more than one class. In such cases+ the certification should be for a product belonging to the same classes. I II III I$ $ $I $II $III IY Y YI YII YIII YI$ Y$ Medicines containing penicillin Medicines containing cephalosporin $accines or sera 'terile medicines <ormones and steroids Microdose preparations other than )itamins#+ i.e. containing 9 mg or less per unit dose Antineoplastic agents and immunosuppressant agents other than steroids# 'olid dose forms Recombinant DNA medicines Metered dose aerosol preparations 0i;uids+ creams+ ointments Non3metered dose aerosols Powders ?ound dressings Transdermal patches

1105

'ites which Manufacture Ful2 Acti.e 6harmaceutical &ngredients

>)idence of GMP or at least e)idence that a bul8 acti)e pharmaceutical ingredient is manufactured consistentl* and to acceptable ;ualit* standards# is re;uired for all sites which manufacture bul8 acti)e pharmaceutical ingredients. 'uch e)idence should be included with each application or notification which relates to a change of site. Applications and notifications must include the name and address of the actual site of manufacture and applicants should ensure that there is no confusion between sites of manufacture and addresses of compan* head offices or bro8ers. An* documentar* e)idence of GMP must refer to the actual site of manufacture.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

An* of the following are acceptable as e)idence for manufacturers of bul8 acti)e pharmaceutical ingredients& A GMP certificate or inspection report issued b* a recognised authorit*. Note that not all authorities issue certification for sites manufacturing bul8 acti)e substances. A Drug Master Bile or e;ui)alent data submitted as part of the dossier for a new chemical entit* or new biological entit* medicine. A >uropean Pharmacopoeial KCertificate of 'uitabilit*L for a substance controlled according to the >uropean Pharmacopoeia. 1atch anal*tical data demonstrating consistent ;ualit* of the substance produced accepted as ade;uate e)idence onl* for lower ris8 medicines and related products#. Note: A GMP certificate alone is not acceptable as a substitute for a DMB+ Certificate of 'uitabilit* or batch anal*tical data where these are normall* re;uired.

1108

Recognised Authorities

GMP certification issued b* the authorities listed below is recognised b* Medsafe. The authorities listed include the competent authorities in the >uropean Communit*+ member authorities of the PIC and.or PIC.' organisations+ and other authorities where Medsafe has information that GMP assessment s*stems that are compatible with New ,ealand e(pectations e(ist. The inclusion of all the >uropean Communit* competent authorities is a conse;uence of the Mutual Recognition Agreement in Relation to Conformit* Assessment that became effecti)e between New ,ealand and the >uropean Communit* on ! Panuar* !""". =mission of an authorit* from the list generall* indicates that Medsafe has not assessed that authorit*-s s*stems+ and should not be construed in an* wa* as an ad)erse reflection on the competence of the authorit* itself. The inspectorates recognised b* Medsafe are listed below. Australia Therapeutic Goods Administration+ Commonwealth Department of <ealth and Bamil* 'er)ices Austria Pharmaceutical Di)ision+ Bederal Ministr* of <ealth+ 'ports and Consumer Protection 1undesministerium fur Gesundheit und Gonsumentenshut/# Felgium Inspection general de la Pharmacie+ Ministere de la 'ante Publi;ue et de la Bamille (anada Therapeutic Products Directorate+ <ealth Product and Bood 1ranch+ <ealth Canada (@ech Re)u*lic 'tate Institute for Drug Control !enmar2 Medicines Di)ision+ Danish Medicines Agenc* 'undhedsst*relsen# Finland National Agenc* for Medicines France Agence du Medicament+ Ministere de la 'ante Germany 1undesministerium fur Gesundheit

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

The indi)idual medicine inspectorates for the different German states and cities+ as listed in the Pharmaceutical Inspection Con)ention 0ist of Inspectors >mplo*ed b* the PIC.' Competent Authorities+ CState9 Name of Authorit* Cit*#D are as follows& #aden-$%rttemberg RegierungsprZsidium T[bingen+ 0eitstelle Ar/neimittel3[berwachung 1aden3?[rttemberg T[bingen# #ayern Regierung )on Mittelfran8en Ansbach# Regierung )on Niederba*ern 0andshut# Regierung )on =berba*ern M[nchen# Regierung )on =berfran8en 1a*reuth# Regierung der =berpfal/ Regensburg# Regierung )on 'chwaben Augsburg# Regierung )on Anterfran8en ?[r/burg# #erlin 0andesamt f[r Gesundheitsschut/+ Arbeitsschut/ und technische 'icherheit 1erlin# #randenburg 0andesamt f[r 'o/iales und $ersorgung ?[nsdorf # #remen 'enator f[r Gesundheit+ Pugend+ 'o/iales und Amwelt3schut/ 1remen# Hamburg 1eh\rde f[r Arbeit+ Gesundheit und 'o/iales <amburg# Hessen RegierungsprZsidium Darmstadt Darmstadt# &ec'lenburg-(orpommern Ar/neimittel[berwachungs3 und Spr[fstelle Mec8lenburg3$orpommern 'chwerin# )iedersachsen 1e/ir8sregierung 1raunschweig 1raunschweig# 1e/ir8sregierung <anno)er <anno)er# 1e/ir8sregierung 0[neburg 0[neburg# 1e/ir8sregierung ?eser3>ms =ldenburg# 1e/ir8sregierung Arnsberg Arnsberg# 1e/ir8sregierung Detmold Detmold# 1e/ir8sregierung D[sseldorf D[sseldorf# 1e/ir8sregeirung G\ln G\ln# )ordrhein-$estfalen 1e/ir8sregierung M[nster M[nster# *heinland-Pfal+ 0andesamt f[r 'o/iales+ Pugend und $ersorgung Goblen/# Saarland Ministerium f[r Brauen+ Arbeit+ Gesundheit und 'o/iales 'aarbr[c8en# RegierungsprZsidium Chemnit/ Chemnit/# RegierungsprZsidium Dresden 'achsen# RegierungsprZsidium 0eip/ig 0eip/ig#

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

Sachsen-,nhalt 0andesamt f[r $ersorgung und 'o/iales 'achsen3Anhalt <alle a.d. 'aale# Schleswig-Holstein 0andesamt f[r Gesundheit und Arbeitssicherheit des 0an3des 'chleswig3<olstein Giel# -h%ringen Th[ringer 0andes)erwaltungsamt ?eimar# For immunologicalsC Paul3>hrlich3Institut+ Bederal Agenc* for 'era and $accines Greece National Drug =rganisation >.=.B.# 7ungary Drug Inspectorate+ National Institute of Pharmac* &celand 'tate Drug Inspectorate &reland Irish Medicines 1oard &taly Pharmaceutical Di)ision+ Ministr* of <ealth Ministero della 'anita+ Dire/ione Generale del 'er)icio Barmaceutico# Ga)an Pharmaceutical Affairs 1ureau+ Ministr* of <ealth and ?elfare iechtenstein Gontrollstelle fur Ar/neimittel+ Amt fur 0ebensmittel8ontrlle u1em*ourg Di)ision de la Pharmacie et des Medicaments Netherlands Pharmaceutical Inspectorate+ 'ection Pharmaceutical Industr* and Trade Ministerie )an $ol8sge/ondheid+ ?el/iNn en 'port+ Inspectie )oor de Ge/onheids/org# Norway Pharmaceutical Inspectorate+ Pharmaceutical Department+ <elsedire8toratet 0egemiddela)delingen# 6ortugal Pharmacies and Pharmaceutical Inspections Department Instituto Nacional da Barmacia e do Medicamento 3 INBARM>D# Romania 'tate Institute for Drug Control and Pharmaceutical Research 'inga)ore Ministr* of <ealth+ National Pharmaceutical Administration 'lo.a2 Re)u*lic 'tate Institute for Control of Drugs

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

')ain Ministerio de 'andidad * Consumo+ 'ubdireccion General de Barmaceutico 'weden Pharmaceutical Inspectorate+ Medical Products Agenc* 0a8emedels)er8et# 'wit@erland For sera and !accinesC =ffice Bederal de la 'ante Publi;ue For other -harmaceutical -roductsC =ffice Intercantonal de Controle des Medicaments "nited Hingdom Medicines Control Agenc*+ Department of <ealth "'A Bood and Drug Administration

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

'ection 1+:

a*elling and 6atient &nformation

Section summary "his section& -ro!ides guidance on the la+elling re uirements for -roducts e>-lains how to su+mit new and changed la+els for a--ro!al e>-lains how and when to a--ly for a la+elling e>em-tion Legislation to read in conjunction with this section Medicines Regulations 1&2.C 1art 9VC =a+elling Regulation 2C 9nter-retation Regulation '0C *afety %ontainers :mendment No 6 Medicines Regulations 1&2. Medicines :mendment Regulations 2000 Misuse of 7rugs Regulations 1&00 Regulation 2$C =a+elling of %ontainers

1+01

a*elling of Medicines and Related 6roducts

The Medicines Regulations Part I$ and subse;uent Amendments thereto set out the re;uirements for the labelling of medicines and related products. 'ponsors must ensure labels include all the information re;uired b* legislation+ and that the appearance and la*out of the label are designed to ma(imise the safe use of the medicine. Medicines Amendment Regulations %222 ha)e remo)ed some of the re;uirements in the original Regulations to pro)ide greater fle(ibilit*+ bring the re;uirements into better harmon* with those appl*ing in Australia+ and remo)e trade barriers. * as a .lassification Statement In addition to the changes to the legislation indicated abo)e+ Medsafe accepts KR(L as a s*mbol meaning Kprescription medicineL where it is clearl* used as a classification statement on a medicine label. Note that R( printed as a blue s*mbol on a *ellow cross centred on a blue s;uare with rounded corners is a protected brand mar8 owned b* the Pharmac* Guild of New ,ealand Inc.# and is not to be confused with R( used as a classification statement.

1+0+

'u*mitting New and (hanged Medicine a*els

Copies of artwor8 for labels and pac8aging material+ including actual si/e copies and an indication of the intended colours must be submitted with an* NMA or NRPA and with an* CMN or CRPN in)ol)ing an* change to the labelling. If colour samples of the actual label are not a)ailable at the time of application or notification+ these must be submitted to Medsafe as soon as possible once the label is printed. ?hen submitting a label for a new medicine or a notification of a change to a pre)iousl* appro)ed label+ the applicant must complete the appropriate 0abelling Chec8list see Appendices " 3 !!# designed to ensure that the label is in compliance with the legislation. The applicant must then also sign a declaration stating that the label complies with the legislation or identif* those aspects in which the label is non3compliant. If the label is non3compliant+ the applicant should first in)estigate the possibilit*

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

of a compliant label e.g. b* o)erlabelling#+ or determine whether the criteria for re;uesting a labelling e(emption could be met. Prior assessment+ through a CMN+ is re;uired for an* labelling change that changes the actual information not merel* the colour or print st*le# relating to the name+ strength of acti)e ingredient+ dosage instructions or warning statements+ or results in the label becoming non3compliant+ or is the result of the medicine being re3classified as a Controlled Drug. Note that changing the location of some information on the label could ma8e the label non3compliant. An* other change to a label ma* be self3assessed b* the applicant and notified through a 'elf3 assessable Change Notification. 'uch changes do not re;uire prior appro)al and ma* be implemented immediatel*. 'ponsors should note that Medsafe carries out random audits of self3assessable changes and+ where an* significant problem is identified+ the sponsor is as8ed to rectif* it. Note that a 'ACN cannot be submitted for consent for a label that has been the subNect of a labelling e(emption and is now compliant with the re;uirements. This re;uires+ instead+ a CMN for a labelling change Grade %. ?hen a CMN is submitted for a change to a label+ a cop* of the current label and the artwor8 for the new label must be included with the chec8list and declaration.

1+03

a*elling (hec2lists and !eclarations

A completed 0abelling Chec8list and signed declaration see Appendices 63!!# must accompan* e)er* application for appro)al of a new or changed medicine or related product label. Three )ersions of the chec8list are pro)ided. If the product is a %edicine including a Controlled Drug# but is not a contact lens solution# use the Medicine 0abelling Chec8list. If the product is a contact lens solution use the Contact 0ens 'olution 0abelling Chec8list. If the product is a related product use the Related Product 0abelling Chec8list. ?here a product has both a primar* container e.g. bottle+ )ial# label and an outer pac8age e.g. carton# label+ both labels must be chec8ed for compliance with the legislation. >ach section of the chec8list must be completed& If the section is not rele)ant to the product label being assessed+ tic8 the KN.AL not applicable# bo(. If the product label meets all the re;uirements listed in a section+ tic8 the KWesL bo( for that section. If the product label does not meet one or more of the re;uirements listed in the rele)ant section+ tic8 the KNoL bo( and highlight the particular re;uirement s# that are not met. If appropriate+ the non3 compliance of the label ma* be e(plained in a co)ering letter. If there is an* doubt about the compliance of a label with the re;uirements+ Medsafe-s ad)ice should be obtained. An applicant wishing to mar8et a %edicine with a non3compliant label must either amend the label to ma8e it compliant or appl* for a labelling e(emption. 'ee also 'ection !%.4 and Medicines Regulation !% 9#. A labelling e(emption cannot be granted for a Related Product or a Controlled Drug. It is acceptable for a New ,ealand label to include the Australian Register of Therapeutic Goods registration number R ((((((#. It is also acceptable for a label to include a barcode. A single chec8list is used to assess the primar* container and secondar* pac8age labels where the product is pac8aged in a strip pac8 inside a carton. In an* other situation where the primar* container is enclosed in a secondar* container e.g. a bottle or )ial enclosed in a cardboard bo(# the primar* container and the secondar* pac8age labels must each be assessed for compliance with the re;uirements

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

in the legislation. In this case+ a separate chec8list should be completed and submitted for the container and outer pac8age labels. Normall* onl* one declaration form co)ering both labels needs to be signed and submitted with the labels and chec8lists. <owe)er+ if one label is compliant and the other is non3compliant+ separate declarations should be completed for each label. In signing the declaration+ the applicant accepts legal responsibilit* for the compliance of the label s# with the legislation. The product ma* ha)e to be recalled from the mar8et if non3compliance is later identified.

1+05

a*elling E1em)tions

Regulation !% 9# of the Medicines Regulations !"64 ma8es pro)ision for a labelling e(emption to be granted to allow a medicine to be mar8eted with a label that does not meet the labelling re;uirements of the Medicines Regulations. A labelling e(emption ma* be re;uested using the CMN form. A completed labelling self3assessment chec8list highlighting the areas of non3compliance should accompan* the CMN. A labelling e(emption is not re;uired when o)erstic8ing of labels occurs in order to bring them into compliance with the regulations+ but the o)erstic8ing must be carried out in premises licensed for labelling or o)erlabelling and compl*ing with GMP re;uirements. ?here a product is manufactured+ pac8ed and labelled o)erseas it is not necessar* for the label concerned to include the name and address of the New ,ealand sponsor or distributor Csee regulations !: !# 8#+ !: %# b#+ !4 !# h#+ and !4 %# b# of the Medicines Regulations !"64D. 0abelling e(emptions cannot be granted for related products or controlled drugs+ or when an* non3 compliant aspects of a label create a safet* problem for New ,ealand prescribers+ dispensers or consumers. 0abelling e(emptions are considered on a case3b*3case basis and ma* be granted when& low sales )olume for the product i.e. :222 or less units per *ear+ or the sponsor can Nustif* a higher limit# mean that the cost of amending the label would not be reco)erable or temporar*+ unforeseen stoc8 shortfalls occur re;uiring the importation of product with non3 compliant labels and the aspect in which the label is non3compliant is considered immaterial to the safe use of the product and is unli8el* to cause confusion or misuse of the product. ?hen a labelling e(emption is granted+ the appro)al letter will indicate the period up to a ma(imum of % *ears# for which the e(emption applies. If an* change is made to a label that is the subNect of a labelling e(emption+ a new labelling e(emption must be re;uested or+ if applicable+ a re;uest must be made for appro)al of the new label through a CMN for labelling change Grade %. 'uch label changes are not self3assessable. A labelling chec8list must be completed and submitted along with an* re;uest for a renewal of a labelling e(emption. The applicant should chec8 that the labelling e(emption is still needed and that an e(emption has not become redundant because of changes in labelling re;uirements. A labelling e(emption will not be granted in an* situation where use of the non3compliant label could be unsafe or cause confusion. La1elling e5e%ptions cannot 1e granted +or )elated Products or Controlled 0rugs.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

Note: Inclusion of a product information leaflet or CMI leaflet that is inconsistent with the appro)ed New ,ealand data sheet is not permissible+ e)en when a labelling e(emption has been granted for use of a non3compliant label. Also+ it is not permissible for the consumer information panel CIP# to be printed on the inside of a container and a labelling e(emption will not be granted for such placement of the CIP.

1+08

$.erla*elling or $.erstic2ing a*els

=)erstic8ing of labels to ma8e them compliant with New ,ealand legislation is permitted. <owe)er+ the o)erlabelling must be carried out either at a site that is currentl* appro)ed for pac8aging of the product concerned+ or at another site whose current pac8ing licence allows o)erlabelling of the product or o)erlabelling in general in this case a CMN or CRPN is re;uired to register the o)erlabelling site for the product concerned and o)erlabelling must not commence until the Director3General-s consent has been granted#. ?here a product is wholl* manufactured and pac8ed o)erseas it is not necessar* for the label to bear the name and address of the New ,ealand distributor. If it becomes necessar* to o)erstic8 the label in New ,ealand to ma8e it compliant with New ,ealand regulations e.g. b* adding the re;uired classification statement# then it is not also necessar* to add the name and address of the New ,ealand distributor to the label. =)erlabelling under these circumstances is not considered to be a manufacturing or pac8ing process in terms of regulations !: 8# %# b# and !4 h# %# b# of the Medicines Regulations !"64. ?here a sponsor has an* ;uestions relating to the suitabilit* of a site for o)erlabelling or re3pac8ing# of a product+ such ;uestions should be addressed to the local Medicines Control office.

1+09

6hysician4s 'am)le 6ac2s

A medicine label must include dosage instructions if the product is intended to be supplied as a gift or sample for the purposes of promoting a sale. This re;uirement applies regardless of whether the product is a prescription or an =TC product. Thus all ph*sician-s sample pac8s must+ in addition to meeting other labelling re;uirements+ be labelled with the dosage instructions for the product.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

1+0:
1+0:01

'mall (ontainers
$#( medicines

Regulation %2 of the Medicines Regulations !"64 describes the information that must be presented on the Consumer Information Panel CIP# of the label of a medicine intended for =TC sale. If it is not possible to print all the necessar* information on the CIP+ then a separate information sheet is permitted for =TC medicines. 'uch information sheets are considered to be part of the labelling of the medicine+ and as such are assessed and appro)ed in the same wa* as the label. In this case+ reference to where the information can be located must be made on the container label. It is not acceptable to ha)e an* part of the CIP printed an*where on the inside of a container or pac8age. Information sheets produced under regulation %2 differ from Consumer Medicine Information leaflets or product information leaflets pro)ided for consumers or prescribers see 'ections !%.!! and !%.!%#.

1+0:0+

'mall .olume medicines and related )roducts

Regulation !7 !# a# iii# of the Medicines Regulations !"64 as amended in the Medicine Amendment Regulations %222 describes the information that must be presented on the labels on small primar* containers ampoules+ )ials+ dental cartridges+ etc.# of sterile medicines where !# the containers are too small to bear all of the information normall* re;uired on the label and %# the containers are not intended for separate sale and :# the* are contained in a full* labelled secondar* pac8age. The labels on the indi)idual primar* containers need onl* include the product-s trade name if an*# and the acti)e ingredient s#+ but the label on the secondar* pac8age e.g. carton# must include all of the information described in regulation !: medicines# or regulation !4 related products#. Bor safet* reasons+ it is strongl* recommended that the strength of the acti)e ingredient s# is also indicated on the primar* container s#.

1+0;

#ransdermal 6atches in 6ouches or 'achets

Transdermal patches that do not contain a Controlled Drug and are pac8aged in pouches or sachets# of an* si/e need onl* bear the following information on the pouch or sachet& product trade name name and strength of each acti)e ingredient batch number e(pir* date

pro&ided all of the following conditions are met& the pouches are contained in an outer pac8age e.g. carton# that is full* labelled in accordance with the Medicines Regulations the pouches are not for indi)idual sale the product is not a Controlled Drug

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

1+0<
1+0<01

'afety (ontainers
!efinition and use of safety containers

A safet* container is defined in the Medicines Regulations Csee regulation % !#D as a container+ such as a strip container composed of aluminium foil or blister tra*s of metal or plastic laminates+ which is reasonabl* resistant to attempts b* *oung children to open it. ?here plastic is used+ it need not be opa;ue. Transparent plastic is permitted b* Amendment 7 to the Medicines Regulations. Regulation :5 of the Medicines Regulations !"64 re;uire that solid dose forms of oral medicines containing an* of the following substances are re;uired to be supplied in a safet* container& Aspirin and its salts Iron+ where the medicine contains more than %4 mg elemental iron per dose Paracetamol 1arbiturates Phenothia/ine and deri)ati)es of phenothia/ine and their salts e(cept dimethothia/ine+ methdila/ine+ prometha/ine+ trimepra/ine+ and their salts and molecular compounds Tric*clic+ tetrac*clic and analogous antidepressants Paracetamol tablets or capsules ma* be distributed to pharmacies in bul8 ;uantities in bottles rather than in safet* pac8aging for unit dose dispensing pro)ided the bul8 containers ha)e the following warning prominentl* displa*ed on the label& N=T B=R G>N>RA0 DI'P>N'ING =R R>TAI0 'A0>. B=R ANIT D='> DI'P>N'ING =N0W. There is no legal re;uirement for manufacturers to suppl* an* li;uid medicines with child resistant closures+ howe)er+ manufacturers of these medicines are strongl* encouraged to do so.

1+0<0+

a*elling of safety containers

Regulation :5 :# of the Medicines Regulations !"64 defines the re;uirements for the labelling of safet* containers for the medicines listed abo)e in 'ection !%.".!. If the medicine is pac8aged in strip3pac8s+ each strip must state the batch code and each indi)idual unit container e.g. blister# must be labelled with the medicine-s trade name+ acti)e ingredient s# and strength. If there is insufficient space on the safet* container for this information+ onl* the trade name of the medicine is necessar*. It is strongl* recommended that the e(pir* date should also be mar8ed on each strip. Regulation !7 defines the re;uirements for the labelling of safet* pac8ages for medicines other than those listed abo)e in 'ection !%.".! and related products. If the medicine is pac8aged in strip3pac8s+ each strip rather than each indi)idual blister# must state the batch code+ the medicine-s trade name and acti)e ingredient s#. If a related product is pac8aged in strip3pac8s+ each strip must state the product-s trade name and batch code. If a strip3pac8 strip is perforated and li8el* to be sold or dispensed in portions+ it is re;uired that each perforated portion should state the trade name of the product. In all cases+ the outer pac8aging that encloses the safet* containers must be labelled with all information re;uired for a medicine label.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

1+01,

')ecific 6ac2aging and a*elling Re?uirements for (ertain Medicines

Certain re;uirements+ in addition to the usual labelling re;uirements for medicines+ appl* to a number of products and t*pes of products. Regulation %% of the Medicines Regulations !"64 re;uire special warnings on the labels of the following t*pes of product& ntihista%ines must bear a warning about the danger of impairment of abilit* to dri)e a )ehicle or operate machiner*. Products containing aspirin9 salic!la%ide and other salic!lates must bear a warning against prolonged use or administration to children under % *ears of age without medical ad)ice. Products containing paraceta%ol must bear a warning against prolonged use or administration to children under % *ears of age without medical ad)ice. Topical medicines+ related products and cosmetics containing he5achlorophane must bear a warning against use on infants or on burnt or damaged s8in. Medicines containing h!drocortisone or h!drocortisone acetate must bear a warning against use of the product for more than 5 da*s without medical ad)ice if the ailment does not respond to treatment. Additional re;uirements are gi)en in 'ection !%.!2.". Medicines and related products for internal use that contain %ore than 3E eth!l alcohol must bear a warning that the* contain alcohol.

In addition+ certain prescription medicines ma* also be sold without a prescription pro)ided the* are in pac8s that meet specific pac8aging and labelling re;uirements. 'pecific re;uirements for particular medicines are detailed in the following subsections. Note that words of similar meaning are acceptable.

1+01,01

Anti=an1iety or anti=insomnia medicines

'edating antihistamines and an* other =TC medicines indicated for insomnia or an(iet* ma* be sold as Restricted Medicines when the following conditions appl*. Those medicines which are for insomnia or an(iet* and which do not fulfil these conditions must be sold as prescription medicines. 1ac3 si)eC <seC Not more than !2 doses Bor short3term use onl* Not for children under !% *ears Do not e(ceed ma(imum stated dose Consult a doctor if sleeplessness or an(iet*# persists.

8arning statementsC Note:

Normal sedation warnings appl* for sedating antihistamines. 'ee Medicines Regulations !"64+ regulation %%#

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

1+01,0+

Antihistamines

Regulation %% of the Medicines Regulations !"64 re;uires antihistamines to be labelled with a warning& K1e cautious about dri)ing a )ehicle or operating machiner* within 6 hours of ta8ing this medicine.L The same regulation also pro)ides for the Director3General of <ealth to grant an e(emption from this re;uirement. Non3sedating Ksecond generationL# antihistamines+ while not ha)ing a sedating effect on most people+ ma* still ha)e a sedating effect on some indi)iduals+ and are re;uired to carr* the following warning on their labels& KAlthough the medicine is unli8el* to affect *our abilit* to dri)e or operate machiner*+ a few people ma* be impaired and care should be ta8en.L

1+01,03

Flood )roducts

0abels for blood components distributed b* the New ,ealand 1lood 'er)ice are not re;uired to compl* with the Medicines Regulations. These labels must compl* with the re;uirements stated in the Minimum *tandards for the %ollection, 1rocessing and Juality :ssurance of Blood and Medicines 7eri!ed from (uman Blood and 1lasma published b* the New ,ealand 1lood 'er)ice.

1+01,05

(ontact lens solutions

Contact lens solutions or tablets for the preparation of solutions#+ must ha)e the following information on the label& Trade name and a description of the preparation e.g. sterile cleaning solution# on the principal displa* panel Instructions for use. 'pecif* the minimum )olume re;uired for use+ whether suitable for boiling+ time for procedures etc. The label ma* refer to the product information leaflet. Net contents Name and address of manufacturer or distributor >(pir* date 1atch number Name s# and strength s# of preser)ati)es and an* other materials critical to the biological performance of the solution e.g. wetting agents. A minimal disclosure of ingredients is permissible pro)ided written assurance is gi)en that a full disclosure of composition is a)ailable on re;uest. Name s# of the lens or lens t*pe with which the solution ma* be used+ or a statement that the solution should not be used with a particular t*pe of lens. Precautions for use. Actions which must be ta8en to a)oid or minimise ha/ards. Include warnings against direct application of the solution to the e*e+ if applicable+ and against mi(ing or dilution of the solution with another+ transferring it to another container other than the lens case+ or re3using it. >(pir* date of solutions applied directl* to the e*e once the container is opened. In addition to the abo)e label re;uirements+ product information should indicate the tonicit*+ p< and buffering properties of the solution.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

1+01,08

(ontrolled !rugs

Regulation %9 of the Misuse of Drugs Regulations !"55+ and subse;uent amendments+ outline the re;uirements for labelling of Controlled Drugs. The labelling re;uirements of the Medicines Regulations must also be met for Controlled Drugs+ e(cept where the re;uirements of the two pieces of legislation are in conflict+ in which case the Misuse of Drugs legislation ta8es precedence. An* controlled drug named in Part $I of the Third 'chedule to the Misuse of Drugs Act and fulfilling the specified re;uirements is b* definition a pharmac*3onl* medicine and can be labelled as such in accordance with the Medicines legislation. The label is not re;uired to include the words C=NTR=00>D DRAG. All other controlled drugs must be labelled in accordance with the Misuse of Drugs Regulations.

1+01,09

(orticosteroids as a?ueous solutions for nasal inhalation

0ow dose beclomethasone+ budesonide+ flunisolide+ fluticasone and mometasone a;ueous nasal preparations ma* be sold as Restricted Medicines for use in the proph*la(is and treatment of seasonal allergic rhinitis when the following conditions appl*& "y-e of -re-aration *trength Non CBC a;ueous formulations 1eclomethasone not more than 92 mcg per actuation 1udesonide not more than 92 mcg per actuation Blunisolide not more than %9 mcg per actuation Bluticasone not more than 92 mcg per actuation Mometasone not more than 92 mcg per actuation Not more than %22 doses 'hort term :37 months# proph*la(is or treatment of seasonal allergic rhinitis ha* fe)er# in adults and children aged !% *ears and o)er. 1eclomethasone Ma(imum of 422 mcg %22 mcg in each nostril# per da* in di)ided doses. 1udesonide Ma(imum 422 mcg %22 mcg in each nostril# per da* in di)ided doses. Blunisolide Ma(imum dail* dose as a single dose or in di)ided doses& Adults %22 mcg !22 mcg in each nostril# Children !% to !7 *ears# !92 mcg 59mcg in each nostril# Bluticasone Ma(imum dail* dose %22 mcg as a single dose Mometasone Ma(imum dail* dose %22 mcg as a single dose <se Do not e(ceed ma(imum stated dose. Dose should be reduced for maintenance treatment once full effect

1ac3 *i)e 9ndications 7osage

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

obtained. Do not use for more than 7 months e(cept on medical ad)ice. 8arning *tatements 'ee8 medical ad)ice before using product name# if *ou are alread* ta8ing another steroid product+ e.g. tablets+ asthma or nasal inhaler or e*e.nose drops. 'ee8 medical ad)ice before using product name# if *ou ha)e infection in the nasal passages or sinuses. 'ee8 medical ad)ice before using product name# if *ou ha)e recentl* had an inNur* or surger* to *our nose+ or problems with ulceration in *our nose. 'ee8 medical ad)ice if nasal s*mptoms are not relie)ed after 5 da*s of treatment. ?hile using product name# see8 medical attention if *ou de)elop& signs or s*mptoms of infection such as& 3 fe)er+ nasal or facial pain or swelling 3 purulent Ki#e# -us4containingL or discolored nasal discharge 3 bleeding from the nose 3 acute e*e pain or )isual disturbance. %ontraindications :d!erse effects :dditional 8arnings and 1recautions As per data sheet As per data sheet As per data sheet

1+01,0:

Fluoride ta*lets

0abels for fluoride tablets should include dosage instructions that are consistent with the Ministr* of <ealth-s recommendations that& tablets should not be used during pregnanc* because there is no firm e)idence of benefit from use of fluoride tablets b* pregnant women and in line with the general polic* that unnecessar* medicines should be a)oided during gestation#. fluoride tablets should onl* be used in areas where there is less than 2.: part per million fluoride in the water suppl* the dosages for different age groups should be& : to 9 *ears& 2.%9 mg elemental fluoride per da* 7 to 6 *ears& 2.9 mg elemental fluoride per da* " *ears and o)er& !.2 mg elemental fluoride per da* CNote that 2.%9 mg elemental fluoride is e;ui)alent to 2.99 mg sodium fluoride.D fluoride tablets should be either chewed thoroughl* or dissol)ed in drin8ing li;uid before swallowing.

1+01,0;

7e1achloro)hane

All =TC products containing he(achlorophane must carr* a warning that the product should not be used on infants without the ad)ice of a registered medical practitioner.

1+01,0<

7ydrocortisone to)ical medicines "!

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

All =TC topical products containing h*drocortisone should bear the following warnings& CAATI=N S Do not use for children under % *ears unless a doctor has told *ou to. Do not use for more than 5 da*s unless a doctor has told *ou to. Do not use under waterproof bandages unless a doctor has told *ou to. Do not use in e*es. Do not use for acne.

1+01,01,

7+=Antagonists

0ow dose presentations of cimetidine or ni/atidine ma* be sold as restricted %edicines+ and low dose presentations of famotidine or ranitidine ma* be sold as phar%ac!7onl! %edicines+ when the following conditions appl*& 1ac3 si)e 9ndications 8arning statements Not more than !4 da*s- suppl* when used at the recommended dose. '*mptomatic relief of heartburn+ d*spepsia and h*peracidit* =R on the recommendation of a medical practitioner. Do not use the medicine for an* purpose other than that specified on the pac8 unless under the super)ision of a doctor. Consult a doctor if s*mptoms persist+ recur or worsen. Consult a doctor if new or additional s*mptoms occur. Do not use with non3steroidal anti3inflammator* medicines unless under the super)ision of a doctor. Ase with caution if o)er 42 *ears of age. In the case of cimetidine+ do not use without medical super)ision if ta8ing warfarin+ phen*toin or theoph*lline.

1+01,011

&*u)rofen li?uid

0i;uid ibuprofen ma* be sold as a Pharmac*3=nl* medicine when the following conditions appl*& *trength 1ac3 si)e 9ndications Must not e(ceed !22 mg ibuprofen per 9ml. Not more than %22 ml Relief of pain and reduction of fe)er and inflammation. Note that Nu)enile rheumatoid arthritis is not an appro)ed indication for the =TC sale of ibuprofen li;uid .

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

7osage

Dose is of the order of %2 mg.8g.da* and generall* meets the following recommendations& Age !3% *ears :35 *ears 63!% *ears 'ingle dose 92 mg !22 mg %22 mg

The dose should be gi)en : to 4 times a da*+ if necessar*. Bor children weighing less than :2 8g the total dose gi)en in %4 hours should not e(ceed 922 mg. 8arning statements Ase of the medicine without a doctor-s ad)ice is contraindicated in& children aged less than !% months children weighing less than 5 8g children suffering deh*dration through diarrhoea and.or )omiting children with gastric ulceration+ indigestion+ stomach pain+ or bleeding children who ha)e pre)iousl* shown h*persensiti)it* to aspirin+ ibuprofen+ or other N'AIAs. This medicine should N=T be ta8en without medical super)ision b*& children who ha)e impaired renal function children who are ta8ing other medicines children suffering from asthma+ urticaria or rhinitis. Consult a doctor if s*mptoms persist for more than : da*s.

1recautions

1+01,011

&odine

The labels of =TC products for internal use that contain iodine should bear the following statements& Caution 3 total iodine inta8e ma* e(ceed recommended le)el when ta8ing this preparation ?arning 3 contains iodine 3 do not ta8e when pregnant e(cept on a ph*sician-s ad)ice.

1+01,01+

6aracetamol

The Ministr* of <ealth-s guidelines for paracetamol dosage are as follows& ge :3!% months !39 *ears 73!% *ears ]!% *ears Single dose 723!%2 mg !%23%92 mg %923922 mg 9223!222 mg

?here these doses do not coincide with standard dose form+ doses should be recommended to the nearest half tablet or %.9 ml. 0i;uid dose forms should be consistent in strength+ i.e.+ !%2 mg.9 ml or %92 mg.9 ml. Reser)e the %92 mg.9 ml concentration for adults %92 mg is accepted+ rather than %42 mg+ as it is e;ui)alent to half of a standard tablet#.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

'olid dose forms for adults should be multiples of %92 mg or 922 mg onl*+ whereas solid dose forms for children should be multiples of 72 mg to be consistent with li;uid dose forms for children. Dosages for tablets should be e(pressed as the appropriate number of whole tablets or half tablets using the abo)e table+ instead of specif*ing the milligram dose. Tablets should preferabl* be scored to allow accurate brea8ing in half+ but smaller fractions are not recommended. Capsules are not readil* or accuratel* di)isible into hal)es. Therefore+ doses of less than whole capsules should not be recommended. "se of )aracetamol with other medicines in the one )roduct #or adults+ combination products which contain paracetamol+ should normall* contain standard doses of paracetamol+ although there ma* be e(ceptions. #or children 12 !ears o+ age or less+ the medicines in combination+ particularl* analgesics+ should be in lower doses than the appro)ed standard doses administered separatel*.

1+01,013

6holcodine

Pholcodine+ when compounded in a li;uid preparation as a linctus is considered b* the Ministr* of <ealth to be a Pharmac* =nl* Medicine Controlled Drug Class C7#.

1+01,015

6regnancy test 2its

In New ,ealand pregnanc* test 8its are classed as general sales medicines+ whereas in most other countries the* are classed as medical de)ices. The following guidelines ha)e been de)eloped to ensure general harmon* between the labelling re;uirements for these products in New ,ealand and Australia. 10 1uter carton The re*uire%ents for the labelling of outer carton are that the following detail must be included& Trade Name The words KPregnanc* Test GitL+ unless these are included in the Trade name The number of pregnanc* test 8its in the carton The name and address of the manufacturer or sponsor The batch number The e(pir* date

Recommended storage conditions are not re;uired if the 8its are to be stored at room temperature in New ,ealand 20 $nner pouch containing actual test kit The reco%%endations for the labelling of the pouch es# containing the actual test 8it s# are that+ as a minimum+ the following detail should be included& The batch number The e(pir* date 0 $nstructions for use At least one cop* of the instructions for use must be included. These instructions ma* be printed on the carton or pouch or be supplied as a pac8age insert. The instructions must include& Directions for use of the reaction de)ice and the urine dropper if an*#

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

Direction to allow the de)ice to return to room temperature before use if it has been stored in a refrigerator Directions with a clear diagram# for appl*ing urine to the reaction de)ice Information on minimum and ma(imum times to wait before reading the result A diagrammatic e(ample of a positi)e result Information on false positi)e.negati)e results

1+01,018

'odium )hos)hate in oral *owel )re)arations

'odium phosphate is classified as a restricted %edicine when contained in oral preparations for bowel cleansing prior to diagnostic+ medical or surgical procedures+ but it is classified as a prescription %edicine when used as a la5ati&e. No sodium phosphate product mar8eted as a restricted medicine ma* contain an* reference to use as a la(ati)e in the pac8age information+ data sheet or CMI.

1+01,019

#o)ical medicines

'ome patients ma* ha)e allergies to certain ingredients e.g. peanut oil# used in some topical medicines. To assist such patients in a)oiding contact with these allergens+ it would be helpful for ingredients of topical medicines to be listed on the label or in product information leaflets. At its meeting on !4 Pune %22!+ the Medicines Ad)erse Reactions Committee recommended that all ingredients+ including preser)ati)es+ of topical medicines be re;uired to be listed in the labelling.

1+01,01:

#o)ical medicines li2ely to *e used in the genital area

'ome ingredients e.g. mineral oils and paraffin wa(es# used in the formulation of topical creams+ ointments+ foams and pessaries rapidl* degrade late( rubber on contact. In order for doctors and pharmacists to be ade;uatel* informed+ the distributors of topical medicines li8el* to be applied to the male or female genital area must ma8e a)ailable information about the compatibilit* of their products with late( rubber. This information should be included in the data sheet for prescription medicines and on the product label or pac8age insert for =TC medicines. 0ate( rubber condoms mar8eted in New ,ealand are re;uired b* law to conform to the International 'tandard I'= 42543!&!""7 ># 3 Rubber Condoms. In accordance with this standard the pac8aging is re;uired to include ad)ice to consult a doctor or pharmacist about the compatibilit* of condoms with prescription or o)er3the3counter topical medicines that are applied to the penis or )agina.

1+011

6roduct &nformation eaflets

Applicants must indicate when a product is to be mar8eted with an enclosed product information leaflet+ and must declare that the information contained in the leaflet is consistent with the appro)ed New ,ealand data sheet or the New ,ealand appro)ed details for the product+ unless some of the content is considered to be an e(tension to the labelling+ in which case this section onl* will be e)aluated. ?here there are inconsistencies+ the compan* must either amend the leaflet or remo)e it from the pac8s to be sold in New ,ealand. These leaflets are neither e)aluated nor appro)ed. The onus is on the applicant to ensure and confirm to Medsafe that the information is consistent with the appro)ed data sheet and details appro)ed b* Medsafe. As these product information leaflets do not form part of the label+ labelling e(emptions cannot be granted to allow the inclusion of a leaflet that is inconsistent with the New ,ealand appro)ed details for the product.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

1+01+

(onsumer Medicine &nformation

Consumer Medicine Information CMI# is accessible and understandable information about medicines written for consumers in accordance with the current edition of New Zealand Regulatory Guidelines for Medicines Volume .C %onsumer Medicine 9nformation# This can be downloaded from the Medsafe web site. A Microsoft ?ord template for preparing CMI is also a)ailable on the web site. ?hile producing CMI is not mandator* New ,ealand currentl* has no legislation regarding CMI#+ sponsors are encouraged to do so. The pro)ision of CMI will help consumers use medicines safel* and effecti)el*. CMI should not be submitted with an NMA or CMN. It should+ instead+ be sent direct to the CMI Co3 ordinator at Medsafe.

Note: I+ a product in+or%ation lea+let has the content or intent o+ Consu%er -edicine In+or%ation and the sponsor would li6e it pu1lished on the -edsa+e we1 site9 then it %ust 1e su1%itted as C-I in accordance with )ew /ealand *egulatory Guidelines for &edicines (olume 0" .onsumer &edicine 1nformation2
CMI for Prescription and Restricted medicines must be based on the appro)ed New ,ealand data sheet. Bor Pharmac* =nl* and General 'ales medicines+ CMI is to be based on the appro)ed New ,ealand data sheet. If there is no such data sheet+ CMI for Pharmac* =nl* and General 'ales medicines can be based on an* of the following appro)ed source documents& Australian Prescribing Information or CMI AG data sheet or CMI A'PDR document Canadian Product Monograph >uropean 'ummar* of Product Characteristics Compan* international prescribing information.

Bor all CMI the sponsor must ensure that& the safet* information in the New ,ealand CMI is consistent with that in the appro)ed source documentF and an* re;uirements in 'ection !:.7 of these Guidelines are also included in the CMIF and the content of the CMI is consistent with the terms of New ,ealand appro)al for the product.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

'ection 13:

!ata 'heets

Section summary "his sectionC -ro!ides detailed guidance on the -re-aration and su+mission of data sheets e>-lains the -rocess for a--ro!ing and -u+lishing new and u-dated data sheets Legislation to read in conjunction with this section Medicines Regulations 1&2. 1art M ARegulations $14$.BC 7ata *heets "hird *cheduleC 7ata sheet re uirements

1301

&ntroduction

Part Y of the Medicines Regulations re;uires sponsors to submit for appro)al data sheets for new and changed prescription or restricted medicines. Data sheets are not re;uired for pharmac*3onl* or general sale medicines or for related products. ?hen a material change is made to an appro)ed medicine+ and that change affects the information in the data sheet+ the data sheet must be amended and submitted for appro)al. The appro)al of the Director3General of <ealth is re;uired before a new or updated data sheet can be published. The legislation relating to data sheets is prescripti)e and somewhat outdated. It was written for a paper3 based s*stem and does not ta8e account of the efficiencies and opportunities offered b* the electronic storage and publication of information. Therefore+ Medsafe has implemented a modified approach to the preparation+ submission+ appro)al and publication of data sheets that will be efficient and resource3 sparing for all concerned+ and will mo)e data sheets into the electronic era. =nce processed and appro)ed+ data sheets will be electronicall* stored and published on Medsafe-s web site. Data sheets are not legall* re;uired for pharmac*3onl* and general sales medicines. <owe)er+ it ma* be appropriate for data sheets to be prepared and submitted for such medicines that are commonl* prescribed. The onus is on sponsors to determine if this would be appropriate and submit a data sheet for appro)al and publication on Medsafe-s web site. The data sheet ma* be based on an* of the o)erseas appro)ed documents listed in 'ection !:.% and the content of the data sheet must be consistent with the terms of New ,ealand appro)al for the product and must include an* re;uired safet* warnings. Data sheets are not re;uired for related products and+ if submitted+ will not be processed or published on Medsafe-s web site. Note+ also+ that if a product is mar8eted under two or more names+ separate data sheets are re;uired for each name of the product concerned. The following sub3section pro)ides detail on how to prepare a data sheet for a prescription or restricted medicine+ either b* amending an o)erseas3appro)ed document+ or b* starting from scratch where there is no such Osource- document a)ailable. Note that+ in addition to the limited chec8ing of data sheets that ta8es place during the appro)al and publication processes+ Medsafe also carries out random audits of published data sheets from time to time. If problems are identified+ these are brought to the attention of the sponsor concerned and the appropriate correcti)e action is re;uested.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

130+ 130+01

6re)aring a !ata 'heet for A))ro.al Format

Data sheets will be accepted in an* of the following formats including section headings#& N,3format data sheet+ as described in the Medicines Regulations !"64 AG data sheet >A 'ummar* of Product Characteristics Product information published in the A'A Ph*sicians Des8 Reference PDR# Canadian Product Monograph >nglish )ersion# Australian Product Information PI#+ or Pharmaceutical compan* international prescribing information document.

The paper cop ies# should be headed with the words KData 'heetL+ but this should be omitted from the electronic cop*. The template used to format data sheets for the web site automaticall* adds the heading. The data sheet both paper and electronic copies# must also include the KDate of PreparationL+ which is the date da*+ month and *ear# that particular )ersion of the data sheet was prepared for submission. The date of preparation must be changed each time an updated )ersion is prepared+ so that onl* one date of preparation appears on each data sheet. This date will be used to identif* that particular )ersion of the data sheet as it progresses through the stages of being proposed+ appro)ed or superseded.

130+0+

(ontent

The data sheet must contain all the information re;uired in a New ,ealand data sheet+ but the information does not ha)e to be presented in the particular order or under the e(act headings specified in the New ,ealand legislation. A data sheet submitted for appro)al in New ,ealand can ha)e the same content as an* of the following documents for the same medicine& Medsafe3appro)ed data sheet an* data sheet published on Medsafe-s web site# AG3appro)ed data sheet >A3appro)ed 'ummar* of Product Characteristics Product information published in the A'A Ph*sicians Des8 Reference PDR# Canadian Product Monograph >nglish )ersion# Australian3appro)ed Product Information PI#+ or Internationall* appro)ed pharmaceutical compan* prescribing information document+

pro!ided it has been amended where necessar* to include& information on presentation+ indications+ dosage+ medicine classification+ pac8age ;uantities and name and address of distributor that is specific to the product as appro)ed in New ,ealand. This information must be amended carefull* so that the data sheet accuratel* describes the product appro)ed in New ,ealand. It is not permissible for a data sheet to show indications or dosages+ or to list strengths or dose forms+ that are not appro)ed in New ,ealand. The indications+ dosages and other New ,ealand3specific information such as product presentation must be chec8ed for consistenc* with the New ,ealand appro)al and amended where necessar*. an* additional N,3specific safet* information re;uested b* Medsafe+ often on the recommendation of an ad)isor* committee. The term Ksafet* informationL refers to all the information about& actions+ pharmaco8inetics+ contraindications+ warnings and precautions+ ad)erse effects+ interactions+ o)erdosage+ pharmaceutical precautions+ and an* Kfurther informationL to be included in a data

"6

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

sheet. ?here an o)erseas3appro)ed source document is used+ the safet* information from that source document should be reproduced unchanged in the data sheet e(cept where there are specific New ,ealand re;uirements. Apart from an* New ,ealand3specific safet* information+ the safet* information in the data sheet should be the same as that contained in the source document. It is not necessar* to re3format the document or to change the headings. If onl* pro)isional consent for distribution of the medicine under section %: of the Medicines Act has been granted+ this fact should be included in the data sheet+ along with an* ga/etted conditions appl*ing to its distribution. An* conditions should be detailed using the wording in the New Zealand Ga)ette notice. Regulation 9: 4# and 94 7# of the Medicines regulations !"64 re;uire that a New ,ealand data sheet must not contain comparati)e data or an* other reference to an* medicine or brand of medicine other than the product that is the subNect of the data sheet.

130+03

6re)aring a new data sheet for which there is an acce)ta*le source document

The source document used in preparing a data sheet must be either the prescribing information document currentl* appro)ed o)erseas as described abo)e or a Medsafe3appro)ed data sheet. ?hen a compan*-s international prescribing information document is used+ the document must be current. It is helpful if the document shows the date on which it was appro)ed for use b* the compan*-s international head office. ?hate)er document is used+ it must be amended to include New ,ealand3specific product+ indications and dosage+ and safet* information. The source document for a multi3source medicine is the data sheet for the inno)ator product+ amended where necessar* to reflect the appro)ed details of the multi3source product e.g. product name+ description+ appro)ed indications+ and sponsor details#. If it is not appropriate to include all of the inno)ator-s indications+ this should be e(plained and Nustified in a co)ering letter. The data sheet for a multi3source medicine must contain the same indications+ dosage and safet* information as the Medsafe appro)ed data sheet for the inno)ator product e(cept where all of the indications appro)ed for the inno)ator product ha)e not been appro)ed for the multi3source product because the* were not applied for in the original multi3source NMA or in a subse;uent CMN+ or there is still patent protection of one or more of the indications appro)ed for the inno)ator-s product#. The indications appro)ed for the corresponding inno)ati)e product are not automaticall* appro)ed for a multi3source medicine. >ach must be applied for as part of the original NMA or a subse;uent CMN.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

130+05

6re)aring a data sheet for which there is no acce)ta*le source document

?here there is no Medsafe appro)ed data sheet and no o)erseas3appro)ed source document+ the data sheet should be prepared in the New ,ealand format set out in the New ,ealand Medicines Regulation !"64. 1efore submission to Medsafe+ the data sheet must be assessed b* the applicant for compliance with the re;uirements of the legislation and these guidelines. A self3assessment chec8list is pro)ided at the end of this subsection to assist applicants in chec8ing data sheet drafts.

A0 (ontent and layout for New Zealand=format data sheets


The following general principles should be ta8en into account when preparing a New Zealand format data sheet& ?here practicable+ all dose forms mar8eted under the same trade name should be included in a single data sheet. It ma* be appropriate for some information to be repeated under different headings. Promotional statements are not permitted in data sheets. Reference to another medicine is not allowed unless it aids the understanding of the proper use of the medicine described in the data sheet. The word ^medicine^ is used to indicate a therapeutic substance. In New ,ealand+ the word ^drug^ indicates a substance of abuse. 1ibliographic references are not to be included in the data sheet. Data sheets should contain information under the following section headings+ in the order gi)en below. ?here no rele)ant information is a)ailable+ the word ^Nil^ should appear under the heading. Name of medicine Presentation includes dose form and strength+ and fla)our if applicable# Ases 3 Actions+ Pharmaco8inetics+ Indications Dosage and administration Contraindications ?arnings and precautions Ad)erse effects Interactions =)erdosage Pharmaceutical precautions Medicine classification Pac8age ;uantities Burther information Name and address Date of preparation

Name of Medicine The proprietar* name+ the name of each acti)e ingredient and the strength s# should be included. If there is no trade name+ the sponsor-s name should be included. A ;ualit* reference to the Ph >ur+ 1P or A'P for the dose form can be also included in this section. There is no need to include headings for the ^Trade name^+ ^Multi3source name^+ KINNL etc.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

6resentation The colour+ dimensions and other ph*sical characteristics of the product s#. A new paragraph should be used for each dose form. "ses The subheadings KActionsL+ KPharmaco8ineticsL and KIndicationsL appear under this heading. #ctions The pharmacological.pharmacod*namic properties that are rele)ant to the therapeutic purpose+ including& pharmacotherapeutic group mechanism of action if 8nown# pharmacod*namic effects for which there is e)idence of a relationship with the therapeutic effect+ or which ma* induce ad)erse reactions. The onset and duration of action should also be included. Bor anti3bacterial agents the following format is recommended& General properties of the agent+ e.g. class+ nature and mode of action+ information on concentration3 dependent bactericidal acti)it* 'usceptibilit* data based on in !itro tests using no less than !22 strains of each species recentl* isolated. New ,ealand3specific data should be presented when a)ailable. A list of susceptible+ intermediate and resistant organisms+ indicating the MIC range for each susceptibilit* categor*. 9n !itro data where clinical efficac* has been demonstrated and is reflected in the appro)ed indications. 9n !itro data should also be included where clinical efficac* is un8nown but susceptibilit* of the organism ma* be rele)ant to the appro)ed indications. A statement should be included to indicate that there is a ris8 of therapeutic failure and this ris8 must be weighed against the potential benefit. A list of species where man* strains show intermediate susceptibilit*+ with an indication of whether and how clinical successes ha)e been obtained for such strains. The information could refer to the occurrence of resistance in special areas of the 'outh Pacific and describe the therapeutic implications of that situation. 'usceptibilit* data should be tabulated as follows&
Species The species should be listed alphabeticall* in the following categories& aerobic gram positi)e organisms aerobic gram negati)e organisms anaerobic organisms other micro3organisms )esistance group or 2 or C ?here A E resistance not *et described 1 E resistance occurs in !23 92@ C E inherent resistance or resistance fre;uentl* occurring ]92@# -IC range +or organis%s without 6nown resistance %echanis%s The MIC range is necessar* onl* for antibiotic.species combinations for which there is clinical rele)ance

Burther detail+ including the in !itro methods inoculum si/e+ source of strains and number of strains#+ should appear in the GBurther InformationL section.

!2!

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

Pharmacokinetics General characteristics& absorption 3 bioa)ailabilit* of each dosage form and information on whether oral dose forms are affected b* li)er first pass effect+ incomplete absorption+ or the presence of food distribution 3 plasma protein binding+ )olume of distribution+ tissue and.or plasma concentrations biotransformation 3 to acti)e metabolites or inacti)e metabolites+ and in the case of prodrugs+ to the acti)e substance elimination 3 elimination half3li)es+ total clearance+ e(cretion route s# for unchanged substance and metabolites. Characteristics in patients& an* 8nown relationship between plasma.blood concentrations and therapeutic acti)it* or ad)erse reactions )ariations with respect to confounding factors 3 age+ pol*morphic metabolism+ concomitant pathological situations renal failure+ hepatic insufficienc*#. $ndications The indication s# appro)ed b* Medsafe+ related as precisel* as possible to the results of clinical trials. A description of the purpose of the medicine. !osage and Administration This should include& dose+ dose inter)al and duration of treatment timing in relation to food dosage adNustment with renal or li)er insufficienc*+ dial*sis+ or concomitant disease ma(imum tolerated dail* dose if rele)ant# ad)ice on monitoring an* procedural steps critical to safe administration of the medicine with reference+ where appropriate+ to each age categor* neonates+ children+ adults and the elderl*#.

(ontraindications 'ituations where patients should ne)er be treated with the medicine+ or generall* should not be treated. In cases where the medicine should ne)er be gi)en+ these must be specificall* stated. Warnings and 6recautions Information intended to& warn prescribers of the possibilit* of ad)erse reactions+ including habituation+ occurring under normal conditions of use or in particular situations such as renal+ hepatic or cardiac failure inform prescribers of the recommended wa*s to pre)ent the occurrence or the worsening of these ad)erse reactions b* patient monitoring+ dose reduction or discontinuation of treatment+ and describe the conditions under which the medicine ma* be recommended for use in sub3groups of patients at ris8+ pro)ided that the special conditions of use are fulfilled. Pregnancy and 2actation 'uitabilit* for use in pregnanc* and lactation. Bor medicines where there is e(tensi)e therapeutic e(perience+ the Australian or A' or 'wedish# categorisation s*stem for safet* in pregnanc* should be used. =ne of the se)en class statements from the Australian Therapeutic Goods Administration TGA# publication 1rescri+ing medicines in

!2%

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

-regnancy, .th edition pre)iousl* called Medicines in 1regnancy# should be included where possible. Copies of this publication can be obtained from the TGA web site& http:www.health.go&.au=tga. Bor medicines with limited therapeutic e(perience this section should include& conclusions from animal reproduction.fertilit* studies and the human e(perience the ris8 in humans during each trimester+ as assessed from the abo)e the ris8 of using the medicine in fertile and pregnant women. If the acti)e substance or an* of its metabolites is e(creted in human mil8+ a recommendation to stop or continue breast feeding+ and the li8elihood and degree of ad)erse reactions in the infant. Effects on a,ility to drive and use machines ?hether the medicine is& a# b# c# d# presumed to be safe or unli8el* to produce an effect+ or li8el* to produce minor or moderate ad)erse effects+ or li8el* to produce se)ere ad)erse effects or presumed to be potentiall* dangerous+ and an* rele)ant warnings or precautions.

1ther 'ignificant preclinical safet* findings including those from in !itro mutagenicit* or carcinogenicit* studies#. ?here further e(planation is warranted the detail can be inserted under Further 9nformation# Ad.erse Effects Information on& significant ad)erse effects obser)ed+ or the most predictable ad)erse effects on the basis of to(icolog*+ especiall* findings from repeated dose to(icit* studies fre;uenc* of these effects and their seriousness pre)ious clinical e(perience with medicines of the same class+ where rele)ant. The data should identif* whether a causal association is li8el* or unli8el*. Reactions should be listed according to fre;uenc*. A tabular presentation is preferred. All ad)erse reactions with a pre)alence of !@ or more should be included. An* serious ad)erse reactions+ and an* others specified b* the Medicines Ad)erse Reaction Committee+ should also be included. If a narrati)e description of ad)erse reactions is used+ the following words should be used to describe pre)alence& Kcommon.fre;uentL E !@ Kuncommon.infre;uentL E T !@ but 2.!@ KrareL E T 2.! @ &nteractions Information on& interactions with other medicines or other substances abnormal laborator* test results associated with the medicine the effect of concomitant use of medicines+ including herbals the effect of dail* acti)ities e.g. meals and consumption of alcohol.

=nl* interactions that ha)e been obser)ed+ or for which there is potential based on clinicall* meaningful e(perience with medicines of the same pharmacotherapeutic group+ need to be included.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

The following information should be gi)en for each interaction& mechanism of action if 8nown# effect on plasma le)els of other medicines and.or effect on laborator* and clinical parameters recommendations such as dose adNustment+ contraindication+ precautions for use etc. $.erdosage The s*mptoms and treatment of o)erdosage+ including& human e(perience management of o)erdose in human acute e(perience in animals 6harmaceutical 6recautions $nstructions for 3se4Handling ?here appropriate& a direction that the product+ as presented+ is not intended for immediate use and has+ for instance+ to be suspended or diluted before administration. There ma* be circumstances where this ad)ice should be included under ODosage and Administration-. Details on compatibilit* should be included here instructions on using.handling the medicine ad)ice that a particular dosing de)ice is needed to administer the medicine $ncompati,ilities ?here appropriate information on& ph*sical and chemical incompatibilities with other medicines with which it is li8el* to be mi(ed or co3administered. This is particularl* important for medicines re;uiring dilution before parenteral administration significant problems of absorption or adsorption to s*ringes+ large )olume parenteral containers etc. +helf 2ife The shelf life of the medicine& pac8aged for sale after first opening the container where appropriate# following dilution or reconstitution according to the directions where appropriate# +pecial Precautions for +torage The ma(imum or minimum# storage temperatures stated in C. If the medicine is stable at temperatures up to :2C+ special storage instructions are not needed. 'tate an* special precautions regarding humidit* and light see 'ection 7.!% for permitted terms#. Medicine (lassification The classification of the medicine 3 Prescription Medicine or Restricted Medicine. 6ac2age Iuantities Pac8 si/es and strengths of each dose form a)ailable in New ,ealand. The OPac8age Huantities- could+ alternati)el*+ appear under the heading OPresentation-. Further &nformation =ther data+ if an*+ not included in pre)ious sections+ such as&

!24

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

summar* information describing clinical trial results information on preclinical test results that could be rele)ant in assessing the ris8.benefit of using the medicine. If the results of preclinical studies do not add to the information needed b* the prescriber+ then the results+ either positi)e or negati)e+ need not be included in the data sheet laborator* details relating to antibacterial agents chemical structure a ;ualitati)e list of e(cipients warnings about the presence of lactose+ gluten or particular colourings+ if appropriate Note: If onl* pro)isional consent for distribution of the medicine under section %: of the Medicines Act has been granted+ this fact should be included in this section+ along with an* ga/etted conditions appl*ing to its distribution. An* conditions should be detailed using the wording in the New Zealand Ga)ette notice. Name and Address The name+ business address in New ,ealand and telephone number of the holder of the consent to distribute. Ba( and e3mail addresses ma* also be included. !ate of 6re)aration The date of preparation da*.month.*ear# of that )ersion of the data sheet.

F0 !ata sheet chec2list


The Data 'heet Chec8list in Appendi( !: is to be used b* applicants when preparing and chec8ing a New Zealand4format data sheet for compliance with the Medicines legislation and the Guidelines. ?here the data sheet does not include information that would normall* be re;uired+ a brief comment should be included on the chec8list to indicate wh* the information was omitted. An e(ample would be KNo data a)ailable on e(cretion in breast mil8L. The chec8list should be forwarded to Medsafe along with the draft data sheet. A chec8list is not re;uired for data sheets prepared using an o)erseas3appro)ed source document.

1303

'u*mitting !ata 'heets for A))ro.al and 6u*lication

The processes for preparation+ submission+ appro)al and publication of draft and final data sheets depends upon the circumstances. Bor an NMA a draft document is to be submitted along with the NMA for re)iew along with the data supporting the NMA. The sponsor ma* be re;uired to modif* the te(t before it can be appro)ed. =nce the NMA has been appro)ed and the Minister-s or Director General-s consent has been ga/etted or con)e*ed b* letter to the sponsor+ the sponsor must submit the final )ersion of the data sheet in both paper and electronic cop* for formal appro)al and publication on Medsafe-s web site. Note that dose forms and strengths and fla)ours of a medicine that ha)e been appro)ed for distribution but are not being mar8eted ma* be left off the data sheet. <owe)er+ it ma* be desirable to print all of the appro)ed dose forms and strengths and fla)ours but ha)e a ;ualifier Ce.g. not mar8eted#D ne(t to the rele)ant dose form.strength.fla)our. ?hen a sponsor subse;uentl* commences mar8eting one or more of these products and wishes to remo)e the words Knot mar8etedL+ this can be arranged b* submitting a self3assessable change

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

notification 'ACN# and fee together with a paper and an electronic cop* of the final )ersion of the data sheet for publication on the web site. 'imilarl*+ if a sponsor wishes to update the safet* information in a data sheet the sponsor must submit a 'ACN and fee together with a paper and an electronic cop* of the final )ersion of the data sheet for publication on the web site. ;hen a data sheet is updated as a result o+ a C-N or S CN9 the date o+ preparation %ust also 1e updated. The sponsor should9 i+ rele&ant9 also consider re&ising an! in+or%ation lea+let=pac6age insert and an! C-I The steps in)ol)ed in the )arious circumstances are gi)en in the subsections below.

130301

NMA for a new chemical or *iological entity medicine or a new .accine

+tep 1 The sponsor drafts a data sheet normall* using an o)erseas3appro)ed source document or compan* head office3appro)ed basic te(t#. +tep 2 The draft and a cop* of the Osource document- if applicable# are submitted to Medsafe along with the NMA and dossier of supporting data. +tep The draft data sheet is assessed along with the NMA and supporting data. An* re;uired changes are communicated to the sponsor b* the MAAC 'ecretar* or $accines 'ub3committee 'ecretar* processing the NMA. There ma* be additional correspondence between the sponsor and the 'ecretar* or e)aluator before the final wording is agreed. =nce the NMA is read* for recommendation for Ministerial consent+ the sponsor is as8ed to submit the final te(t of the data sheet to the Data 'heet Co3 ordinator for processing and publication see step 9 below#. +tep 5 Ministerial consent for the distribution of the new medicine in New ,ealand is ga/etted. +tep 6 ?ithin !4 da*s after ga/ettal of consent+ the sponsor forwards to the Data 'heet Co3ordinator the following& !. The final data sheet on A4 paper %. The final data sheet in electronic form in M' ?ord for ?indows or Rich Te(t Bormat on computer dis8 :. The completed Data 'heet Declaration Borm see Appendi( !%# 4. The source document if applicable#. CNote& Although a cop* ma* alread* ha)e been supplied with the NMA+ a second cop* is re;uired to ensure that it can easil* be located and perused with the final )ersion of the data sheet.D +tep 7 Medsafe processes the data sheet and publishes it on the web site and ad)ises the sponsor that the data sheet has been appro)ed and published. Publication of the data sheet on the web site is part of the appro)al process.# The sponsor should chec8 the published data sheet to ensure that it is correct. =nce the data sheet has been appro)ed+ the sponsor ma* distribute it.

13030+
+tep 1

NMA for a new multi=source medicine

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

The sponsor drafts a data sheet normall* using as the source document the inno)ator-s data sheet as published on Medsafe-s web site#. The onus is on the sponsor to ensure that an* patent protections of particular indications appro)ed for the inno)ator-s product are ta8en into account. +tep 2 The draft and a cop* of the Osource document- are submitted to Medsafe along with the NMA and dossier of supporting data. +tep The essentials of the draft data sheet are assessed along with the NMA and supporting data. An* re;uired changes are communicated to the sponsor b* the Medsafe e)aluator processing the NMA and+ once the NMA is read* for recommendation for Ministerial consent+ the sponsor is as8ed to submit the final te(t of the data sheet to the Data 'heet Co3ordinator for processing and publication see step 9 below#. +tep 5 Ministerial consent for the distribution of the new medicine in New ,ealand is ga/etted. +tep 6 ?ithin !4 da*s after ga/ettal of consent+ the sponsor forwards to Medsafe-s Data 'heet Co3ordinator the following& !. The final data sheet on A4 paper %. The final data sheet in electronic form in M' ?ord for ?indows or Rich Te(t Bormat on computer dis8 :. The completed Data 'heet Declaration Borm see Appendi( !%# 4. The source document if applicable#. CNote& Although a cop* ma* alread* ha)e been supplied with the NMA+ a second cop* is re;uired to ensure that it can easil* be located and perused with the final )ersion of the data sheet.D CNote& If the final te(t is not submitted within !4 da*s of ga/ettal consent+ the sponsor will be reminded to do so. If the data sheet is then not recei)ed within ! month of ga/ettal+ an additional 'ACN fee will be charged. In the meantime+ if the medicine is being mar8eted+ the trade name of the medicine will be published on the web site with the comment Kdata sheet not supplied b* compan* name#- against it.D +tep 7 Medsafe processes the data sheet and publishes it on the web site and ad)ises the sponsor that the data sheet has been appro)ed and published. Publication of the data sheet on the web site is part of the appro)al process.# The sponsor ma* then distribute the data sheet.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

130303

New dose form of an a))ro.ed medicine

+tep 1 The sponsor drafts a data sheet normall* using as the source document the data sheet for the pre)iousl* appro)ed dose form s# of the same medicine as published on Medsafe-s web site#. The data sheet ma* be dose form3specific or it ma* co)er the currentl* appro)ed and the new dose forms. +tep 2 The draft and a cop* of the Osource document- are submitted to Medsafe along with the NMA and dossier of supporting data. +tep The essentials of the draft data sheet are assessed along with the NMA and supporting data. An* re;uired changes are communicated to the sponsor b* the MAAC 'ecretar* or Medsafe e)aluator processing the NMA and+ once the NMA is read* for recommendation for Ministerial consent the sponsor is as8ed to submit the final te(t of the data sheet to the Data 'heet Co3ordinator for processing and publication see step 9 below#. +tep 5 Ministerial consent for the distribution of the new medicine in New ,ealand is ga/etted. +tep 6 ?ithin !4 da*s after ga/ettal of consent+ the sponsor forwards to the Data 'heet Co3ordinator the following& !. The final data sheet on A4 paper %. The final data sheet in electronic form in M' ?ord for ?indows or Rich Te(t Bormat on computer dis8 :. The completed Data 'heet Declaration Borm see Appendi( !%# 4. The source document if applicable#. CNote& Although a cop* ma* alread* ha)e been supplied with the NMA+ a second cop* is re;uired to ensure that it can easil* be located and perused with the final )ersion of the data sheet.D CNote& If the final te(t is not submitted within !4 da*s of consent+ the sponsor will be reminded to do so. If the data sheet is then not recei)ed within ! month of ga/ettal+ an additional 'ACN fee will be charged. In the meantime+ if the new dose form of the medicine is being mar8eted+ its trade name will be published on the web site with the comment that a data sheet for the particular dose form s# of the medicine has not supplied b* the sponsor.D +tep 7 Medsafe processes the data sheet and publishes it on the web site and ad)ises the sponsor that the data sheet has been appro)ed and published. Publication of the data sheet on the web site is part of the appro)al process.# The sponsor ma* then publish the data sheet.

130305

(MN for a new indication andDor new dosage instructions

+tep 1 The sponsor drafts a re)ised data sheet normall* using as the source document the pre)iousl* appro)ed data sheet as published on Medsafe-s web site#. In the case of a multi3source medicine+ the source document will be the inno)ator-s data sheet including the new indication.dosage. The onus is on the multi3source medicine sponsor to ensure that the new indication.dosage is not subNect to patent protection. If a new indication not appro)ed for the inno)ator-s product is being sought+ this will ha)e to be supported b* clinical data. +tep 2

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

The draft and a cop* of the Osource document- are submitted to Medsafe along with the CMN and an* re;uired dossier of supporting data for the new indication and.or dosage instructions. +tep The CMN ma* be processed as a CMN or referred to the Minister under section %4 9# of the Medicines Act and thereafter processed as an NMA+ either b* a Medsafe e)aluator or b* the MAAC. The re)isions to the data sheet are assessed along with the CMN.'%4 9# NMA and supporting data. An* re;uired changes are communicated to the sponsor b* the MAAC 'ecretar* or Medsafe e)aluator processing the CMN.NMA. =nce the new indication is read* for recommendation for the Director General-s or the Minister-s consent+ the sponsor is as8ed to submit the final te(t of the data sheet to the Data 'heet Co3ordinator for processing and publication. The sponsor is also as8ed to notif* Medsafe when the product is to be mar8eted for the new indication.dosage. +tep 5 Ministerial consent for the distribution of the new medicine in New ,ealand is ga/etted. +tep 6 ?ithin !4 da*s after consent is gi)en or ga/etted+ the sponsor forwards to Medsafe-s Data 'heet Co3 ordinator the following& !. The final data sheet on A4 paper %. The final data sheet in electronic form in M' ?ord for ?indows or Rich Te(t Bormat on computer dis8 :. The completed Data 'heet Declaration Borm see Appendi( !%# 4. The source document if applicable#. CNote& Although a cop* ma* alread* ha)e been supplied with the NMA+ a second cop* is re;uired to ensure that it can easil* be located and perused with the final )ersion of the data sheet.D CNote& If the final te(t is not submitted within !4 da*s of consent+ the sponsor will be reminded to do so. If the data sheet is then not recei)ed within ! month of ga/ettal+ an additional 'ACN fee will be charged.D +tep 7 Medsafe processes the data sheet+ publishes it on the web site and ad)ises the sponsor that the data sheet has been appro)ed and published. Publication of the data sheet on the web site is part of the appro)al process.# The sponsor ma* then distribute the data sheet.

130308

New or u)dated safety data

+tep 1 The sponsor prepares a final )ersion of the data sheet incorporating the new information normall* using as the source document a re)ised compan* prescribing information#. In the case of a multi3source medicine+ the source document will be the inno)ator-s data sheet including the new information published on Medsafe-s web site.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

+tep 2 The sponsor submits to Medsafe a self3assessable change notification 'ACN# together with the re;uired fee and& !. The final data sheet on A4 paper %. The final data sheet in electronic form in M' ?ord for ?indows or Rich Te(t Bormat on computer dis8 :. The completed Data 'heet Declaration Borm see Appendi( !%# 4. The source document if applicable#. +tep Medsafe ac8nowledges the 'ACN. CNote that the document is not routinel* assessed b* Medsafe. Appro)al is granted on the basis of the applicant-s signed declaration that either the safet* information is the same as that appro)ed o)erseas or the safet* information meets the re;uirements in the legislation and guidelines and has been appro)ed b* Medsafe and an* N,3specific additional safet* information re;uired b* Medsafe is included.D +tep 5 Medsafe processes the data sheet and publishes it on the web site and ad)ises the sponsor that the data sheet has been published.

130309

Miscellaneous changes to data sheets

?here a sponsor wishes to ma8e minor changes to one or more data sheets e.g. change in name or address of the sponsor+ or changes in the pharmaco8inetic or pharmacod*namic data# such changes should be submitted through a self3assessable change notification 'ACN# listing all of the products concerned. It is necessar* to submit both a paper cop* and an electronic cop* of the actual data sheet s# concerned. Medsafe will then ma8e the necessar* changes to the data sheet te(t s# on its web site. It is important that the changes are clearl* indicated e.g. b* highlighting# on the paper cop*. ?here a significant number of data sheets are in)ol)ed the >)aluation Team 0eader ma* grant a fee discount for bul8. 'ponsors should discuss this option with the Team 0eader.

1305

7el)ful 7ints for 6re)aring !ata 'heets for 6u*lication

File Format Data sheets should be submitted on a !.4Mb :.9 inch I1M PC dis8ette+ either as a Microsoft ?ord for ?indows document or in Rich Te(t Bormat RTB#. The te(t must be clean and not include changes highlighted or struc8 out. The dis8 must be accompanied b* a clean A4 paper cop* of the data sheet. A separate paper cop* highlighting an* changes should also be supplied to assist identification and chec8ing of the changes. #e1t Formatting Do not include the heading KData 'heetL on the electronic cop*. This will be added during Medsafe-s formatting of the document for publication on the Medsafe web site. Bor efficient processing and publication on the web site+ it is essential that data sheets are prepared using standard Kst*lesL. This will result in a standardised format for documents on the web site. Data sheets submitted without using these standard st*les will not be processed and published+ and will be returned to the applicant for re3submission in the re;uired st*le.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

The document must use standard st*les as follows& OTitle- for trade name of the product O'ubtitle- for the acti)e ingredient+ dose form and strength O<eading !-for main section headings such as KAsesL in the N, format# O<eading %- for sub3section headings such as KActionsL in the N, format# O<eading :- for lower le)el headings O<eading 4- for lowest le)el headings ONormal- for all other te(t. ONormal Indent- ma* also be used. An* dot points in the data sheet should be in the O0ist 1ullet- st*le. An* numbered lists should be in the O0ist Number- st*le.

Note: No other st!les should 1e used. There is no special re;uirement for font t*pe or si/e. Pro)ided all the main headings use the st*le K<eading !L+ it does not matter what font si/e this is+ or whether it is bold+ underlined or in italics. ?hen publishing data sheets on the web site+ Medsafe will appl* a macro and use a st*le sheet to con)ert the different fonts and font si/es to a single standard st*le+ gi)ing the published data sheets a uniform appearance. To put a document into the re;uired st*les+ simpl* highlight a heading and select the appropriate st*le from the st*le bo( in *our word processing program. If the specified st*le does not appear in the st*le bo(+ t*pe it in. Normal te(t does not re;uire highlighting as it is a default st*le. More detailed instructions on using st*les can be found in the Regulator* Information section of Medsafe-s web site www.medsafe.go)t.n/#. The na me of the produc t should be in the st*le OTitle-. The gen e ric na me + stre n g t h and dos a g e form should be in the st*le O'ubtitle-. All main he a din g s should be in <eading ! st*le and then desc e n di n g order to <eading 4. The main words in the he a din g s should be a capital letter followed b* lowerc a s e letter s + e.g.+ ODosa g e and Administr a tion- not OD='AG> AND ADMINI'TRATI=N- or ODosag e and ad mi nis tr a tion-. All lines in comp a n * addr e s s e s should end with a 'hift U>nt e r . This re mo) e s the spac e s betw e e n lines. All numb e r e d lists should be in the st*le O0ist Numb e r- and bullet e d lists und er the st*le O0ist 1ullet-. 'ome grap hic s ha)e bee n of a poor sta nd a r d. 1e prep a r e d for re;u e s t s for bett e r diagr a m s . Not e : grap hic s should be as K.gifL or K.NpgL files. Tables re;uire a significa nt amo u n t of forma t ti ng. The ea sie s t wa* of ma n a gi n g this is to ha)e each piec e of dat a in its own cell. Data sep a r a t e d b* use of the >nter 8e* is difficult to line up with corre s p o n di n g dat a in other column s . Do not use tabs or spac e s to align te(t #e1t >mph a si s should not be ma d e b* und erlining the rele)a n t word s# as it can be mist a 8 e n for a h*perlin8 on the web site. Inste a d KboldL the rele)a n t word s#. An* s*mbols used in the data sheet should be inserted from the Character Map. To insert a s*mbol+ open KAccessoriesL+ select KCharacter MapL+ then choose the appropriate s*mbol from the a)ailable options. All _g s*mb ols should be writte n out as mcg or microgr a m s + _0 should be microlitre s + and _mol should be micro mol or micro mol e s .

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

0i;uid me a s u r e m e n t s should be in millilitres+ not tea s p o o n s . The e(pr e s sio n s Kb.i.dL and Kt.i.d.L should prefer a bl* be spelt out in full The degr e e V# s*mb ol should be in Arial font and the easi e s t wa* of doing this is to hold down the OAlt- 8e* and the n 8e* in 2!57. The J s*mb ol is also found in the Arial char a c t e r ma p Oalt- 2!6"#. Apdat e the ODate of Prepa r a tio n- each time *ou ma8 e a cha ng e . (ontent It is )ital that all produc t det ails+ indications and dos a g e s are correct. If in doubt+ cont a c t Meds af e to det e r mi n e the appro) e d indication s. Generic comp a ni e s mus t ha)e all indications appro) e d either at the time of initial appro) al of the gen e ric or later throug h a CMN# 3 the* cannot Nust adopt the inno)a t or-s indication s without notif*ing Meds af e. Generic dat a she e t s mus t be ess e n ti all* similar to the inno)a t or produc t dat a she e t but nee d not nec e s s a ril* ha)e identic al wording. Ma8e sure all sent e n c e s ma 8 e sens e . Meds af e has found ma n * sent e n c e s in draft dat a she e t s that are ambigu o u s or simpl* inco mp r e h e n s i bl e . Administrati.e Indic a t e i+ th e dat a sh e e t is +or a %ar 6 e t e d or no n7 %ar 6 e t e d pro d u c t . This sa)e s Meds af e from ha)ing to cont a c t the spons or to clarif* if the dat a she e t is to be publish e d or not. Non3 mar8 e t e d produc t s are not publish e d on the web site. If a produc t is withdr a w n from the New ,eala n d mar8 e t + ens ur e that Meds af e is ad)is e d. Anless the spons or re;u e s t s other wis e + the dat a she e t will nor mall* re mai n on the web site for % *e ar s from the time of withdr a w al of the produc t. If *ou ha)e an upda t e + plea s e indicat e clearl* the chan g e s ma d e . <owe)e r+ do not use re)ision lines on the electronic cop*. If the cha ng e s are small+ it is some ti m e s ea sier to ame n d the e(isting web cop* rath e r than refor ma t the whole docu m e n t . <owe) e r+ Meds af e still re;uire s an electronic cop*. Note that: It is the spons or-s. a p plic a n t-s respon si bilit* to forma t the dat a she e t as describ e d abo) e+ but ther e is no special re;uir e m e n t to use an* particular font or font si/e. The font and font si/e will be forma t t e d b* Meds af e whe n prep a ring the docu m e n t for publication on the web site. If the docu m e n t is incorr ec tl* forma t t e d + it will be return e d and the ad mi nis tr a tion fee will not be refund e d . If in doubt+ cont a c t Meds af e before sub mit ting the electronic )ersion. If an* minor chan g e s such as punct u a tio n or spelling# ha)e bee n ma d e to the dat a she e t b* Meds af e+ the s e will be indicat e d on the appro) al lett er. All other cha ng e s will be discus s e d with the spons or befor e publication.

1308

(hanges to 6u*lished !ata 'heets

Bor a CMN where the intended changes are to indications or dosage and re;uire amendment of the data sheet+ a draft document is to be submitted with the CMN along with an* data supporting the change. Bor all other CMN changes affecting the data sheet+ a cop* of the re)ised document should not be submitted until consent has been recei)ed for the change. =nce the CMN has been appro)ed the

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

sponsor must submit the amended data sheet in both paper and electronic form together with the declaration and a cop* of the CMN consent letter.

1309

Additional 'afety &nformation Re?uired in New Zealand !ata 'heets

The following safet* information relating to specific medicines and therapeutic groups+ must be included in the New ,ealand data sheet irrespecti)e of how the data sheet is prepared.

130901

&ndi.idual medicines

Anistre)lase 8arningC antibod* persists for at least 4 *ears and re3administration carries a ris8 of allergic reactions and reduced efficac*. Astemi@ole *edation warning 3 see entr* for non3sedating antihistamines. J"4-rolongation and arrhythmias warningC Ris8 factors 3 more than recommended dose+ li)er disease and interacting medicines. Fen@ydamine '*stemic allergic reactions ma* occur with topical use of ben/*damine e.g. lo/enges+ gargle+ oral gel. (ar*ama@e)ine If pregnanc* occurs+ or if considering starting treatment during pregnanc*+ the potential benefits must be carefull* weighed against the possible ha/ards particularl* in the first : months of pregnanc*. (ar*ima@ole :d!erse effectsC agranuloc*tosis and granuloc*topenia. (ila@a)ril :d!erse effects& drop in haemoglobin. (isa)ride %ontraindicationsC Concomitant administration of a/ole antifungalsF macrolide antibiotics such as er*throm*cin+ clarithrom*cin or troleandom*cinF <I$ protease inhibitorsF nefa/odone. :d!erse effectsC Rare cases of cardiac arrh*thmia+ including )entricular tach*cardia+ )entricular fibrillation+ torsade de pointes+ and HT3prolongation ha)e been reported. Most patients were recei)ing multiple other medications and had pre3e(isting cardiac disease or ris8 factors for arrh*thmias. 9nteractionsC The main metabolic pathwa* of cisapride is through CWP:A4. The concomitant oral parenteral use of drugs that significantl* inhibit these en/*mes ma* result in increased plasma le)els of cisapride and could increase the ris8 of HT3prolongation. <ence the concomitant use of the following medicines is contraindicated& a/ole antifungalsF macrolide antibiotics such as er*throm*cin+ clarithrom*cin or troleandom*cinF <I$ protease inhibitorsF nefa/odone. (larithromycin 9nteraction with cisa-rideC prolongation of the HT inter)al and cardiac arrh*thmias. (lo@a)ine 8arnings and -recautionsC Clo/apine use has been associated with )ar*ing degrees of impairment of intestinal peristalsis ranging from constipation to intestinal obstruction+ faecal impaction and paral*tic ileus. =n rare occasions these cases ha)e been fatal. Patients should be warned and ;uestioned about bowel function. :d!erse effectsC Constipation and ileus.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

Note that access to prescribing clo/apine is limited to medical practitioners who are )ocationall* registered under the Medical Practitioners Act !""9 in the branches of ps*chological medicine or ps*chiatr* and medical practitioners emplo*ed as registrars in ps*chological medicine or ps*chiatr* who are under the super)ision of )ocationall* registered specialists in these fields. Practitioners prescribing clo/apine must also compl* with a minimum set of standards such as those contained in the New ,ealand Guidelines for the use of At*pical Anti3ps*chotic Drugs % nd edition+ 'eptember !""6# or the re;uirements of local <ospital <ealth 'er)ice Protocols for the use of Clo/apine. (olchicine 1harmaco3ineticsC The elimination half life is !23:! hours. It increases with renal and hepatic impairment+ and in o)erdose situations. 7osage and administrationC For acute gouty arthritisC It is usual to start with a dose of !.%mg two 2.7mg tablets#. This dose ma* be followed b* ! tablet %3hourl* until the pain is relie)ed or diarrhoea+ or other gastrointestinal s*mptoms+ de)elop. The total dose in an acute attac8 should not e(ceed 7mg !2 tablets total#. It is important to obser)e this ma(imum because of the to(icit* of colchicine+ and the ris8 of serious prolonged diarrhoea. In elderl* patients+ those who are small and slight T928g# and those with renal or hepatic impairment+ other treatments should be considered. If colchicine is used in these patients a lower ma(imum dose :mg# should be obser)ed. 'uch an intensi)e regimen of colchicine therap* should not be repeated until an inter)al of at least three da*s has elapsed between courses+ but maintenance therap* with one tablet could be ta8en the da* following treatment for an acute attac8. ,!erdosageC Patients with a suspected o)erdose of colchicine re;uire close hospital monitoring. Erythromycin 9nteraction with cisa-rideC cardiac arrh*thmias. Flucona@ole 9nteraction with cisa-rideC cardiac arrh*thmias from prolongation of HT inter)al. Fluo1etine Ase with other serotonergic agents ma* lead to serotonin s*ndrome. 9nteraction with warfarinC haemorrhage 8arningC withdrawal effects ma* occur and the dosage ma* need to be tapered on withdrawal in some patients. &tracona@ole Interaction with cisapride& prolongation of the HT inter)al and cardiac arrh*thmias. Hetocona@ole 9nteraction with cisa-rideC prolongation of the HT inter)al and cardiac arrh*thmias. Metformin %ontraindicationsC significant renal impairment serum creatinine ] 2.!7 mmol.0#+ chronic hepatic disease+ conditions associated with h*po(ia e.g. recent m*ocardial infarction+ cardiac failure+ pulmonar* disease and surger*#+ alcoholism. 8arnings and -recautionsC because of the increased ris8 of lactic acidosis+ metformin should be ceased at least 46 hours prior to a procedure or on admission for an emergenc* procedure# predisposing to deh*dration and not restarted until the patient is eating and drin8ing normall*. The glucose le)els of patients in catabolic states+ e.g. sepsis or in the post3operati)e period should be monitored. 'hort term insulin therap* is ad)ised. =ther ris8 factors for lactic acidosis include sepsis+ high dosage of metformin+ increasing age and deh*dration. Metoclo)ramide

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

:d!erse effectsC galactorrhoea nonpuerperal lactation# and ele)ation of serum prolactin le)els ma* occur. Micona@ole 9nteraction with cisa-rideC prolongation of the HT inter)al and cardiac arrh*thmias. Moclo*emide Ase with other serotonergic agents ma* lead to serotonin s*ndrome. Nefa@odone 8arnings and -recautionsC Although there is no e)idence that pre3e(isting li)er disease increases the ris8 of an idios*ncratic hepatic ad)erse drug reaction+ an* patient with compromised li)er function who e(periences an additional hepatic insult ma* be at greater ris8 for a se)ere outcome. Therefore+ in patients with pre3e(isting li)er disease+ the e(tent of hepatic impairment should be assessed when considering initiating nefa/odone treatment. Nefo)am :ctionsC include pharmacological actions+ particularl* anticholinergic and s*mpathomimetic action. Nystatin> oral '*stemic absorption and s*stemic ad)erse reactions+ including h*persensiti)it* reactions ma* occur. $estriol -systemic> not to)ical/ Delete an* statements about endometrial proliferation not occurring. 8arnings and 1recautionsC A population3based case control stud* has shown that oral oestriol !3%mg dail* is associated with an increase in the ris8 of endometrial cancer in postmenopausal women. The o)erall ris8 associated with recent use T ! *ear pre)iousl*# compared with no use was %.4 "9@ confidence inter)al !.63:.2#. The ris8 increased with duration of use and declined rapidl* after discontinuation of hormone use. The stud* pro)ided no information on the relati)e ris8 of endometrial cancer between oestriol and standard potenc* oestrogens+ nor did it in)estigate a possible dose relationship. 'ince endometrial proliferation ma* occur in some women+ c*clic administration of a progestogen ma* be appropriate. This ad)ice could be included in another section.# $estrogens = low )otency -systemic> not to)ical/ Adapt the information under oestriol.# $me)ra@ole :d!erse effectsC h*ponatraemia 6aro1etine 8arningC some patients will e(perience withdrawal effects+ and dosage ma* need to be tapered during withdrawal. 6henyl*uta@one 9ndicationC use in acute flare3ups of an8*losing spond*litis onl*+ because of the ris8 of aplastic anaemia.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

6ro)ofol 7osage and :dministration Asedation during intensi!e careBC There are limited data on propofol safet* at high dosage ] 4 mg.8g.h# for e(tended periods of greater than 46 hours see ?arnings and Precautions#. 8arnings and 1recautionsC 'pecial caution should be e(ercised of infusion rates in prolonged sedation ]46 hours# e(ceed 4 mg.8g.h. In se)erel* head inNured patients also recei)ing incremental inotropic support+ fatal metabolic acidosis or cardiac failure ha)e been reported in association with propofol infusion rates ]9 mg.8g.h for ]96 hours. Re)iew of the sedation regime should be conducted in the presence of une(plained acidosis or cardio)ascular compromise. :d!erse /ffectsC )er* rarel* with prolonged sedation+ metabolic acidosis and cardiac failure. Ris)eridone :d!erse effectsC hepatic reactions. Ro1ithromycin :d!erse effectsC neurops*chiatric reactions ma* occur including agitation+ an(iet*+ confusion+ depression+ sleep disorder+ hallucination. 'ertraline 8arningC some patients will e(perience withdrawal effects+ and dosage ma* need to be tapered during withdrawal. ')ironolactone 'hould not be prescribed for hirsutism in women contemplating pregnanc* and should be considered onl* after other possible measures ha)e been e(plored. 'tre)to2inase 8arningC antibod* persists for at least 4 *ears+ and re3administration carries a ris8 of allergic reactions and reduced efficac*. #amo1ifen :d!erse effectsC There is e)idence of an increased incidence of thromboembolic e)ents+ including deep )ein thrombosis and pulmonar* embolism during tamo(ifen therap*. ?hen tamo(ifen is used in combination with c*toto(ic agents+ there is a further increase in the ris8 of thromboembolic e)ents occurring. 1recautionC According to one stud*+ women who ha)e ta8en unopposed oestrogen therap*+ who are obese+ or who are continuing to ta8e tamo(ifen after therap* for 9 *ears ma* be at greater ris8 for endometrial cancer and consideration should be gi)en to closer monitoring of these groups. #er*inafine :d!erse effectsC neurops*chiatric di//iness+ agitation+ paraesthesia#+ haematological+ s8in and hepatic ad)erse effects. #erfenadine *edation warning 3see entr* for non3sedating antihistamines. :d!erse effectsC HT prolongation and cardiac arrh*thmias. Ris8 factors& more than recommended dose+ li)er disease and concomitant interacting medicines or grapefruit Nuice. #hiorida@ine Ander -herapeutic indications add as the preamble& Thiorida/ine therap* should be initiated onl* b* a specialist and onl* after the patient has failed to respond ade;uatel* to treatment with appropriate courses of at least two other suitable medicines. 3nder Dosage and &ethod of ,dministration add as the preamble& Treatment should be initiated onl* after the patient has been assessed for ris8 factors for HT3prolongation and undergone a chec8 of the HTc3inter)al and serum potassium see ?arnings and Precautions for further details#.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

Dosage and timing of thiorida/ine inta8e should be indi)iduall* adNusted according to the nature and se)erit* of s*mptoms. It is recommended that the initial dose be at the lower end of the ranges mentioned below and be graduall* increased until the full* effecti)e le)el or a ma(imum of %22mg dail* is reached. The total dail* amount is usuall* gi)en in % to 4 di)ided doses. Dosages of more than %22mg dail* should be prescribed onl* in e(ceptional circumstances and onl* under the super)ision of a specialist. If dosages abo)e %22mg are used+ a ma(imum of 722mg dail* should be obser)ed and after e)er* increase in dose the HT c3inter)al should be measured. The >CG should be recorded % wee8s after the increase in dosage and the measurement ta8en !% hours after a dose or immediatel* prior to a dose. The dosage should be adNusted downwards if the HT c3inter)al is 922ms and the patient should be assessed for ris8 factors see ?arnings and Precautions#. Bor patients on a maintenance dose of greater than %22mg dail*+ the >CG should be chec8ed if the patient de)elops a disease state or commences medication that ma* increase the ris8 of HT3prolongation either directl* or indirectl* e.g. b* causing h*po8alaemia#. Paediatric indications& As for adults+ thiorida/ine should be prescribed for children onl* under specialist super)ision paediatrician or child ps*chiatrist#. The ma(imum dose of 4 mg.8g.da* should be obser)ed upper limit %22mg#. Doses abo)e %22mg dail* should be used onl* in e(ceptional circumstances and onl* under specialist super)ision+ and the contraindications+ precautions and monitoring ad)ice should be followed. The dosage instructions for some of the indications will need to be adNusted for consistenc*. 3nder .ontraindications add& <istor* of HT3prolongation+ )entricular arrh*thmia+ torsade de pointes+ and those with ris8 factors for arrh*thmia+ such as second or third degree atrio)entricular bloc8+ clinicall* significant heart disease and congenital long HT3s*ndrome. 1aseline HTc3inter)al 922ms. Abnormal serum potassium. Concomitant use of medicines which inhibit CWP %D7 e.g. cimetidine+ fluo(etine+ paro(etine+ moclobemide+ tric*clic antidepressants# or inhibit metabolism b* another mechanism e.g. flu)o(amine+ pindolol+ propranolol# or cause prolongation of the HTc3inter)al see Interactions#. 3nder $arnings and Precautions add& HT3prolongation& 1ecause of the ris8 of HT3prolongation+ thiorida/ine should be initiated onl* after the patient has been assessed for ris8 factors for HT3prolongation and undergone baseline >CG and serum potassium. Patients with a baseline HT c3inter)al 922ms should not recei)e thiorida/ine. Abnormal serum potassium should be corrected prior to prescribing thiorida/ine. Concomitant medication should also be assessed for substances that inhibit CWP %D7+ inhibit metabolism of thiorida/ine b* another pathwa* or cause HT3prolongation see Interactions#. Ase of thiorida/ine is contraindicated with such medicines. Caution should be e(ercised if the patient is ta8ing a medicine which ma* predispose to h*po8alaemia. 1ecause thiorida/ine is metabolised b* CWP %D7+ patients who are slow metabolisers b* this en/*me are also at increased ris8 of HT3prolongation with thiorida/ine. Bor some patients slow metaboliser status ma* be suspected+ because of e(perience with other agents metabolised b* CWP %D7. A procedure for chec8ing for slow metaboliser status is not widel* a)ailable. Those patients 8nown to be slow metabolisers should not be prescribed thiorida/ine. Patients ta8ing thiorida/ine who ha)e a HT c3inter)al 922ms during treatment should ha)e the dosage adNusted downwards and an assessment conducted for ris8 factors. The continuing prescription of thiorida/ine should be e)aluated in these patients. If the HT c3inter)al is persistentl* 922ms+ or if the patient de)elops a contraindication disease state or medicine#+ thiorida/ine should be discontinued b* gradual dosage reduction o)er a period of a month and concurrent introduction of alternati)e medication. /lderly -atientsC >lderl* patients are more li8el* to ha)e identified or unidentified cardio)ascular disease and special care should be ta8en with regard to the ris8 of arrh*thmias from HT3prolongation in these patients. 3nder 1nteractions add& C*tochrome P492 %D7 metabolism

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

Thiorida/ine is metabolised b* CWP %D7 and is itself an inhibitor of metabolism b* this pathwa*. The effects of thiorida/ine ma* therefore be increased and prolonged b* medicines which inhibit this en/*me+ such as cimetidine+ fluo(etine+ paro(etine+ tric*clic antidepressants and moclobemide. Concomitant use is contraindicated. Meta+olism +y other -athways Certain other agents+ such as flu)o(amine+ pindolol and propranolol+ inhibit the metabolism of thiorida/ine b* other pathwa*s. Concomitant use is contraindicated. "ricyclic antide-ressants 1oth tric*clic antidepressants e.g. amitript*line+ dothiepin+ do(epin+ nortript*line+ clomipramine# and thiorida/ine ma* cause HT c3prolongation. In addition+ most tric*clic antidepressants+ li8e thiorida/ine inhibit CWP %D7+ resulting in possible increases in plasma concentrations of both medicines. Concomitant use is contraindicated. :gents causing J"c4-rolongationC Thiorida/ine is contraindicated with agents which ma* cause HT c3 prolongation including ;uinine+ terfenadine+ astemi/ole+ cisapride+ some antiarrh*thmic medicines e.g. amiodarone+ ;uinidine+ flecainide+ sotalol#+ tric*clic antidepressants and some other antips*chotic agents e.g. droperidol+ haloperidol+ risperidone#. #ia)rofenic acid :d!erse effectsC c*stitis+ which ma* progress to renal failure if tiaprofenic acid is not discontinued. 8arningC use with caution in patients with recurrent urinar* tract infections or c*stitis+ or urinar* s*mptoms from an* cause+ since the s*mptoms of urinar* problems with tiaprofenic acid ma* be mas8ed. 1efore starting treatment with tiaprofenic acid all patients should be ad)ised to contact their doctor if an* urinar* s*mptoms de)elop. Viga*atrin 8arnings and 1recautionsC $isual field defects ma* de)elop with )igabatrin. As*mptomatic effects are common about :2@# but s*mptomatic effects occur infre;uentl* T!@#. It is not clear whether the rate ma* continue to increase with duration of use. $isual field defects with )igabatrin appear to be irre)ersible after discontinuation of )igabatrin. A)ailable data suggest that the pattern of )isual field defects is a concentric constriction of the )isual field of both e*es+ which is generall* more mar8ed nasall* than temporall*. In the central )isual field within :2 degrees of eccentricit*# fre;uentl* an annular nasal defect is seen. Central )isual acuit* is not impaired. Most patients with defects confirmed b* perimetr* ha)e not pre)iousl* noticed an* s*mptoms+ e)en in cases where a se)ere defect was obser)ed in perimetr*. 'igns such as blurred )ision+ diplopia+ peripheral )ision disturbances bumping into furniture+ difficult* in locating obNects in the home or while shopping# ma* be an indication of )isual field constriction. The ris8 of )isual field defects should be considered and the benefit to be e(pected from )igabatrin weighed against the ris8s and benefits of other treatment options before prescribing )igabatrin. If sei/ures are better controlled with )igabatrin than with other agents it ma* be acceptable to ris8 some )isual field constriction+ especiall* if it ma* be as*mptomatic. 'pecial consideration should be gi)en to the use of )igabatrin in children+ since it is not possible to conduct ade;uate )isual field testing in those under a de)elopmental age of !%3!: *ears. Appropriate )isual field testing should be performed at baseline and si(3monthl* thereafter. Patients should be instructed to report an* new )ision problems. If )isual s*mptoms de)elop+ then the patient should be referred to an ophthalmologist for further e)aluation. If )isual field defects are identified+ the decision to continue or discontinue )igabatrin should be based on an indi)idual benefit3ris8 assessment. In patients where )isual field testing cannot be ade;uatel* performed e.g.+ commonl* in *oung children#+ the decision to start )igabatrin should similarl* be based on an indi)idual benefit3ris8 Nudgement. :d!erse effectsC $isual field defects ha)e been reported in patients recei)ing )igabatrin. As*mptomatic )isual field defects are fre;uent whereas s*mptomatic )isual field constriction of )arious degrees is uncommon see ?arnings and Precautions#.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

Warfarin Interaction with oral micona/ole gel to produce an increase in INR and bleeding problems.

13090+

#hera)eutic Grou)s

A(E inhi*itors Not for use in pregnanc*. >mbr*opath* can occur in second or third trimester. Ma* cause pancreatitis. Feta=*loc2ers> including al)haD*eta *loc2ers Contraindicated in asthma or other obstructi)e lung disorders+ uncontrolled heart failure+ cardiogenic shoc8+ sic8 sinus s*ndrome+ grade % and : A3$ bloc8 or se)ere brad*cardia. Fen@odia@e)ines Ma* impair dri)ing. ?ill e(acerbate the effects of alcohol. Can cause blurred )ision.di//iness and impair concentration. Rebound effects ma* occur+ especiall* with short3acting agents. Can cause dependenc* e)en in short term use. Courses should be as brief as possible 3 up to one wee8 for insomnia or three wee8s for an(iet*. Intermittent use ma* be acceptable. After chronic use+ tolerance will occur and doses should be tapered off in withdrawal. (e)halos)orins 'hould not ordinaril* be gi)en to those allergic to cephalosporins or to penicillins+ especiall* where an allergic or urticarial reaction has occurred. !ermal corticosteroids Contraindicated where there is coe(isting infection+ otherwise concurrent antimicrobial therap* re;uired. Not for use in the e*e. Ase in pregnanc* to be limited because of possible teratogenic effects. '*stemic absorption and h*pothalamic3pituitar* a(is suppression ma* occur. Ase for longer than 4 wee8s can cause atrophic striae+ prolonged use on fle(ures and in intertriginous areas is undesirable. Fluoro?uinolones Ma* cause tendinitis+ h*pogl*caemia. 7+=rece)tor antagonists ?hen indicated for the eradication of ( -ylori in patients with peptic ulcer disease& The data sheet should reflect the importance of ( 1ylori in the pathoph*siolog* of peptic ulcer disease and emphasise that eradication of the infection is the single most important therapeutic inter)ention in patients positi)e for (# 1ylori# 7ormone re)lacement thera)y Prolonged monotherap* with oestrogens increases the ris8 of endometrial h*perplasia and carcinoma in post3menopausal women. 'tudies ha)e found that protection from this effect is achie)ed with !2 da*s progestagen therap* per month. There is a small ris8 of breast cancer with the use of hormone replacement therap*. The ris8 increases with duration of use+ but drops to the normal le)el within fi)e *ears of discontinuation of use. ?omen using hormone replacement therap* ha)e less ad)anced breast cancer at diagnosis. The role of progestogens in the ris8 of breast cancer is unclear. Contraindicated in cerebro)ascular or coronar* arter* disease+ cancer+ pregnanc*+ undiagnosed abnormal )aginal bleeding+ thrombophlebitis or thromboembolic processes or a histor* of theseF hereditar* or ac;uired predisposition to )enous thrombosis e.g. antithrombin III deficienc*#. Relati)el* contraindicated in gall bladder disease+ h*pertension+ decreased glucose tolerance+ h*percalcaemia or where there is an hepatic adenoma.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

?arnings should include& The ris8 of )enous thromboembolism is increased with a positi)e famil* histor*+ obesit* bod* mass inde( ]:28g.m%#+ prolonged immobilisation+ surger*+ trauma or se)ere )aricose )eins. If an* signs of thromboembolic processes occur+ treatment should be discontinued immediatel*. An* statements about monitoring patients with a histor* of thromboembolic disorders or other inade;uate precautions should be deleted. :d!erse effectsC s8in rash. 7ormone re)lacement thera)y )roducts with the following indication: AFor a reduction in the ris2 of coronary heart disease -(7!/ in women with no current or )rior e.idence of (7!0B The following warning statement& KIn the <eart and =estrogen3progestin Replacement 'tud* <>R'#+ %57: postmenopausal women with documented coronar* heart disease C<D# who were ta8ing their usual cardiac medications were randomised to conNugated oestrogen-s C># 2.7%9mg plus medro(*progesterone acetate MPA# %.9mg dail* or placebo. Documented C<D was defined as the presence of one or more of the following& pre)ious m*ocardial infarction+ pre)ious percutaneous mechanical re)ascularisation+ pre)ious coronar* arter* b*pass graft surger*+ or angiographic e)idence of greater than 92@ occlusion of one or more maNor coronar* arteries. During an a)erage follow3up of 4.! *ears+ treatment with C> plus MPA did not reduce the o)erall rate of recurrent coronar* heart disease e)ents+ defined as C<D death or nonfatal m*ocardial infarctions+ in this elderl* population a)erage age 77.5 *ears# with established coronar* disease. There was an earl* increase in recurrent C<D e)ents in the first *ear in the C> plus MPA group+ but after two *ears of treatment with C> plus MPA+ a decrease in recurrent C<D e)ents was reported.L &nhaled and intranasal corticosteroids 8arnings and 1recautionsC ad)ice about s*stemic effects and about growth retardation occurring in children. Non=sedating antihistamines *edation warning 3 KAlthough this medicine is unli8el* to affect the abilit* to dri)e or operate machiner*+ a few people ma* be impaired and care should be ta8en.L Non=steroidal anti=inflammatory agents 1arenteralC Contraindicated in patients ta8ing anticoagulants or on intensi)e antidiuretic therap*. ,ral or -arenteralC Contraindicated in patients with gastrointestinal ulceration+ haemorrhagic diasthesis+ asthma. Relati)el* contraindicated in li)er d*sfunction. Dosage should be minimised in the elderl* and in patients with renal impairment. $estrogen=containing contrace)ti.e )ill Contraindicated in women with cancer+ li)er disease+ disturbed lipometabolism+ a histor* of thromboemboli+ hemiplegic migraine+ undiagnosed )aginal bleeding. Ischaemic or haemorrhagic stro8e is more li8el* in women of :9 *ears of age and older who smo8e. Relati)el* contraindicated in women with h*pertension+ cardiac or renal d*sfunction+ diabetes+ migraine+ epileps*+ depression. Ansuitable for use in lactating women. $)ioid analgesics 8arningsC This medicine should not be used for the treatment of chronic pain of non3malignant origin unless& all other conser)ati)e methods of analgesia ha)e been tried and ha)e failed there is no ps*chological contraindication+ drug3see8ing beha)iour or histor* of drug misuse. Therap* should onl* be initiated b* a specialist with e(perience in chronic pain management and in accordance with guidelines appro)ed b* the New ,ealand Medical Association.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

$ral contrace)ti.es containing desogestrel or gestodene %ontraindicationsC A histor* of )enous thromboembolism or hereditar* thrombophilia. ?arnings and precautions& If an* signs of thromboembolic processes occur+ treatment should be discontinued immediatel*. The ris8 of )enous thromboembolism increases with a positi)e famil* histor*+ obesit*+ e(tensi)e )aricose )eins+ immobilisation+ malignanc*+ haemol*tic uraemic s*ndrome and s*stemic lupus er*thematosus. The ris8 is temporaril* increased with maNor surger*+ trauma+ inNur* or temporar* immobilisation. Bour published studies ha)e suggested a higher ris8 of )enous thromboembolism with combined oral contracepti)es containing desogestrel or gestodene than with those containing le)onorgestrel. The absolute ris8 of )enous thromboembolism appears to be appro(imatel* % per !2+222 woman *ears for the oral contracepti)es containing desogestrel or gestodene and ! in !2+222 woman *ears for those containing le)onorgestrel. Bor comparison+ the ris8 associated with pregnanc* is 7 cases per !2+222 pregnant woman *ears. The figures in the four studies point to a higher ris8 with the oral contracepti)es containing desogestrel or gestodene. 1ias and confounding factors ma* partiall* e(plain the difference in ris8. 6rogestogen=only oral contrace)ti.es %ontraindicationsC Current thromboembolic process. Contraindicated in women with a histor* of ectopic pregnanc*+ cancer of breast or genitals. Contraindicated in li)er disease+ disturbed lipometabolism+ se)ere arterial disease+ undiagnosed )aginal bleeding. Relati)el* contraindicated in patients with h*pertension+ diabetes+ migraine+ cardiac d*sfunction+ o)arian c*sts+ malabsorption s*ndrome+ depression. Ase with caution in lactating women since progestogens are found in mil8. Possible loss of effect through interaction with antibiotics+ anticon)ulsants or diminished absorption through diarrhoea or )omiting. Action to be ta8en in the e)ent of a suspected pregnanc*. Ma* enlarge uterine fibroids. Ma* cause certain li)er function tests to be unreliable. 8arnings and -recautionsC There is e)idence that doses of progestogen higher than those used for contraception 93:2mg dail* !s# 2.9mg dail*# ma* be associated with an increased ris8 of )enous thromboembolism. Progestogens at doses used for contraception do not appear to be associated with an increase in ris8 of )enous thromboembolism. Progestogen3onl* contracepti)e pills ma* be considered as an option for contraception in women who ha)e e(perienced D$T or P> with a combined oral contracepti)e+ pro)ided the thromboembolic process has resol)ed. In most cases a progestogen3onl* contracepti)e pill need not be discontinued for maNor surger* in)ol)ing immobilisation. 6rotease inhi*itors 8arnings and -recautionsC There ha)e been reports of new onset diabetes mellitus or h*pergl*caemia+ or e(acerbation of pre3e(isting diabetes mellitus or h*pergl*caemia. 'ome patients re;uired either initiation or dose adNustments of insulin or oral h*pogl*caemic agents for treatment of these e)ents. In some cases diabetic 8etoacidosis has occurred. In the maNorit* of cases+ treatment with protease inhibitors was continued while in some cases treatment was either discontinued or interrupted. In some patients+ h*pergl*caemia persisted after the protease inhibitor was withdrawn+ whether or not diabetes was reported at baseline. :d!erse effectsC new onset of diabetes mellitus or h*pergl*caemia+ or e(acerbation of pre3e(isting diabetes mellitus. 6roton )um) inhi*itors ?hen indicated for the eradication of ( -ylori in patients with peptic ulcer disease& The data sheet should reflect the importance of ( 1ylori in the pathoph*siolog* of PAD and emphasise that eradication of the infection is the single most important therapeutic inter)ention in patients positi)e for (# 1ylori# 6roducts deri.ed from or )urified using human *lood com)onents The data sheet should include the fact that the product is deri)ed from or purified using human blood components and that the ris8 of transmission of some infectious agents cannot be e(cluded completel*.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

#o)ical medicines li2ely to *e used in the male or female genital area Information about the compatibilit* of these products with late( rubber condoms should be included in the data sheet.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

'ection 15:

Fioe?ui.alence and &nterchangea*ility

Section summary "his sectionC defines the choice of reference -roduct for a +ioe ui!alence study lists the -roducts for which com-arati!e +ioa!aila+ility is re uired discusses interchangea+ility and the list of interchangea+le multi4source medicines

1501

&ntroduction

To be appro)ed for distribution in New ,ealand+ a multi3source prescription medicine must usuall* be bioe;ui)alent to the appropriate New ,ealand Reference Product N,RP#. 'imilarl*+ e)idence of bioe;ui)alence will usuall* be re;uired for changes in products where bioa)ailabilit* or clinical efficac* ma* be significantl* altered as a result of the change. >)idence of bioe;ui)alence with a reference product is the surrogate used+ instead of clinical trial data+ to demonstrate safet* and efficac*. =ral dose forms are considered bioe;ui)alent when "2@ confidence inter)als for the ratios of their geometric mean Cma( and AAC from /ero time to infinit* for single doses or within a dosing inter)al at stead* state# are within the range 2.6 3 !.%9 wider limits+ e.g. 2.59 S !.::+ ma* be appropriate for Cma( in certain circumstances where this can be Nustified on clinical grounds#+ and an* difference between their Tma(-s is within clinicall* acceptable limits. The abo)e range is the ma(imum permitted for medicines that present a 8nown or theoretical bioe;ui)alence problem re;uiring an in !i!o bioe;ui)alence stud*. It ma* be tightened for medicines that ha)e& a narrow therapeutic inde( 8nown serious dose3related to(icit* a steep dose.effect cur)e non3linear pharmaco8inetics within the therapeutic dosage range.

1ioe;ui)alence of metered dose inhalers and other inhaler de)ices ma* be established from data establishing ph*sical and clinical e;ui)alence. Procedures for establishing the bioe;ui)alence of oral does forms and inhaled products are outlined in 'ections !9 and !7 respecti)el*. There is no New ,ealand specific guideline for bioe;ui)alence of topical corticosteroid preparations. The A' BDA has published a guideline for establishing the bioe;ui)alence of this t*pe of product entitled "o-ical 7ermatological %orticosteroidsC in !i!o +ioe ui!alence#

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

Note: ?here there is an* doubt about the appropriateness of a bioe;ui)alence stud* age+ design+ choice of reference product+ formulation of the reference product+ or the formulation of the test product+ the applicant is strongl* ad)ised to see8 Medsafe-s ad)ice before submitting the data in support of an NMA or CMN.

150+

(hoice of Reference 6roduct

To establish bioe;ui)alence+ the applicant must pro)ide e)idence that a multi3source product is bioe;ui)alent to the New ,ealand Reference Product N,RP#. In most circumstances+ the N,RP is either the inno)ator product mar8eted in New ,ealand or another product for which Medsafe holds clinical trial and pharmacolog* data. There ma* be more than one reference product+ especiall* where two products ha)e entered the mar8et with clinical trial and pharmacolog* data. ?here there is no ob)ious inno)ator or where the inno)ator product is discontinued+ the reference product is the New ,ealand mar8et leader. It is not essential for the batch of reference product used in the bioe;ui)alence stud* to be sourced in New ,ealand. <owe)er+ when it is sourced outside New ,ealand+ e)idence is re;uired that the foreign3 sourced batch has an identical formulation to the New ,ealand mar8et product. 'uch e)idence usuall* includes most or all of the following& appearance dimensions mean and indi)idual data for !2 dosage units# mean weight and weight uniformit* for %2 dosage units dissolution profiles mean and indi)idual data for 7 dosage units# at : different p<s across the gastro3intestinal range ! to 5.9 Bourier transform infra3red BTIR# spectra of samples+ recorded either as G1r pellets or as pressed powders in a diamond cell+ scaled so that the strongest band in each spectrum is the same height and the spectra can be o)erlaid for comparison powder Y3ra* diffraction YRD# spectra results where practicable# of ;ualitati)e and ;uantitati)e anal*ses of the e(cipients. Bor changed inno)ati)e medicines the reference product will be the formulation pre)iousl* appro)ed and mar8eted.

1503
150301

Fioa.aila*ility !ata Re?uirements


6roduct ty)es that re?uire com)arati.e *ioa.aila*ility data

If a new prescription medicine is intended to be substituted for a product alread* on the mar8et+ bioe;ui)alence with this product should be shown or Nustified. Comparati)e bioa)ailabilit* studies should be carried out when lac8 of bioe;ui)alence ma* be therapeuticall* significant. Therefore+ comparati)e bioa)ailabilit* studies are carried out if there is a ris8 of lac8 of bioe;ui)alence and.or a ris8 of therapeutic failure or diminished clinical safet*.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

Comparati)e bioa)ailabilit* studies are re;uired for the following t*pes of product& !. '*stemicall*3acting oral immediate release products with an* of the following characteristics& indicated for serious conditions re;uiring an assured therapeutic response narrow therapeutic inde( steep dose3response cur)e pharmaco8inetics complicated b*& 3 )ariable absorption 3 absorption less than 52@ 3 non3linear pharmaco8inetics 3 pre3s*stemic elimination.first pass metabolism greater than 52@ high ratio of e(cipients to acti)e ingredients unfa)ourable ph*sico3chemical properties e.g. low solubilit*+ poor permeabilit*+ metastable cr*stalline form+ instabilit*# documented e)idence of bioa)ailabilit* problems either for the particular medicine or other medicines with similar formulations or whose acti)e ingredient s# ha)e similar chemical structures no rele)ant data a)ailable+ unless Nustification b* the applicant that an in !i!o stud* is not necessar* %. Non3oral and non3parenteral immediate release products designed to act s*stemicall* :. Modified release products with a s*stemic action 4. Bi(ed combination products with s*stemic action

15030+

Gustifying not su*mitting com)arati.e *ioa.aila*ility data

?here comparati)e bioa)ailabilit* data are normall* re;uired in an application but the sponsor wishes to omit the data+ Nustification for the omission is re;uired. The following issues should be addressed in the Nustification copies should be pro)ided of an* literature cited#& ?hat is the water solubilit* of the medicineM ?hat is the nature of the dosage formM Bor reformulations and applications for appro)al of a new strength or fla)our of an alread* appro)ed product+ how similar are the formulations of the )arious productsM Bor different strengths+ are the formulations direct scalesM Bor reformulations and applications for appro)al of a new strength of an alread* appro)ed product+ how do dissolution profiles of the )arious products compareM Bor multi3source products+ this ma* include a dissolution comparison of each strength with the corresponding strength of a mar8et leader. If the multi3source and the mar8et leader are supplied in different strengths+ a comparison is still possible in terms of percent label strength dissol)ed against time+ but the Nustification will be less powerful. Is there a first pass effect and is it significantM Are the pharmaco8inetics linearM <ow wide is the margin between the minimum effecti)e and minimum to(ic plasma concentrationsM ?hat are the clinical conse;uences of lac8 of bioe;ui)alence or )ariable bioa)ailabilit* e.g. increased dose leading to to(icit* or decreased dose leading to inefficac*#M Are an* special claims made in labelling or prescribing information about the absorption profileM

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

150303

Medicines not re?uiring com)arati.e *ioa.aila*ility data

New Medicine Applications for the following dose forms or product t*pes do not usuall* need to include comparati)e bioa)ailabilit* data or a Nustification as to wh* the data are not re;uired. =)er3the3counter =TC# medicines. 'imple a;ueous solutions intended for intra)enous inNection. Micellar or liposomal solutions are not regarded as Osimple- solutions. 'olutions+ comple( or simple+ which do not contain pharmacologicall* acti)e ingredients , e.g. artificial tears+ contact lens solutions+ lubricants+ irrigation solutions and cleansing solutions. A;ueous inNections containing the same acti)e ingredients and e(cipients in the same concentrations+ and administered b* the same route s#+ as an alread* appro)ed product. =ral solutions containing the same acti)e ingredients in the same concentration as an oral solution alread* appro)ed+ and where the e(cipients do not significantl* affect gastric passage or absorption of the acti)e ingredients. Powders for reconstitution where the resultant solution meets the criteria for one of the fi)e solution groups abo)e. Topical or locall* acting solutions that ha)e the same formulation. Products containing therapeutic substances which are not s*stemicall* or locall* absorbed e.g. antacids+ anthelmintics+ barium sulphate enemas or oral suspensions+ non3biodegradable ion e(change resins or other non3biodegradable long chain pol*mers+ powders in which no ingredient is absorbed#. If there is doubt as to whether absorption occurs+ a stud* or Nustification ma* be re;uired. $accines clinical trial data are alwa*s re;uired for )accines# Nebuliser solutions Nasal spra*s intended for local action Medicinal gases Monoclonal antibodies Dial*sis solutions Products for which an acceptable correlation has been shown between the dissolution rate in !i!o and in !itro, and the dissolution rate in !itro of the new product is e;ui)alent to that of an alread* appro)ed mar8et leader under the same test conditions as were used to establish the correlation. A product that differs from an alread* appro)ed product onl* in the strength of the acti)e substance does not re;uire bioa)ailabilit* data pro)ided all of the following fi)e conditions are met& !. the pharmaco8inetics of the medicine are linear within the therapeutic dose range+ and %. the products are direct scales or in the case of small strengths+ the ratio between the e(cipients is the same#+ and :. both products are produced b* the same manufacturer using the same manufacturing process+ and 4. a bioa)ailabilit* or bioe;ui)alence stud* has been performed with the original product+ and 9. under the same test conditions+ the dissolution rate in !itro is the same. Note: Products are said to be Odirect scales- onl* if the same granulate or mi(ture of powders is used to manufacture the )arious strengths+ but the products are compressed or filled at )ar*ing weights corresponding to the )arious strengths.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

Products for which the application includes well3performed clinical trials for the patient population and indication applied for# which establishes efficac* comparable to that of the inno)ator.mar8et leader product. These products ma* be appro)ed for distribution e)en though establishing therapeutic e;ui)alence and interchangeabilit* with the inno)ator.mar8et leader product is considered a separate issue

150305

(hanges not re?uiring further *ioe?ui.alence testing

The following changes to alread* appro)ed products do not usuall* re;uire comparati)e bioa)ailabilit* data or a Nustification for the lac8 of data. Immediate release tablets+ capsules and immediate release compressed implants+ suppositories and pessaries& i# Minor adNustments to the ;uantities of currentl* used h*drophilic e(cipients+ including h*drophilic lubricants.glidants+ where dissolution profiles of the new and old formulations ha)e been shown to be in the same range ii# Minor changes to the content of talc where dissolution profiles of the new and old formulations ha)e been shown to be in the same range. Bor detailed guidance on what constitutes a minor or maNor change to these products see the A' BDA guidelines& Guidance for 9ndustry 4 9mmediate Release *olid ,ral 7osage Forms, *cale4u- and 1osta--ro!al %hangesC %hemistry, Manufacturing, and %ontrols, 9n Vitro 7issolution "esting, and 9n Vi!o Bioe ui!alence 7ocumentation Guidance for 9ndustry 4 *<1:%4MRC Modified Release *olid ,ral 7osage Forms, *cale4u- and 1osta--ro!al %hangesC %hemistry, Manufacturing, and %ontrols, 9n Vitro 7issolution "esting, and 9n Vi!o Bioe ui!alence 7ocumentation# Moulded suppositories and pessaries& Minor ;uantitati)e changes in the currentl* used e(cipients where the dissolution profile is in the same range as pre)iousl*+ and 4ither i# Microscopic imaging of particles has shown no )isible change in si/e distribution and morpholog* particle si/ing ma* also be conducted b* other suitable means such as a <egmann gauge#. 5r ii# It has been demonstrated that particle si/e and pol*morphic form of the acti)e raw material are unaltered. If the method used to chec8 pol*morphic form has not been )alidated+ at least two methods should be used including at least one of differential thermal anal*sis and differential scanning calorimetr*. This does not appl* where the acti)e is in solution at an* stage during manufacture of the finished product+ or if it is in solution in the finished product or is present as li;uid globules. Bor detailed guidance on what constitutes a minor or maNor change to these products see the A' BDA guidelines& Guidance for 9ndustry 4 Nonsterile *emisolid 7osage Forms, *cale4u- and 1osta--ro!al %hangesC %hemistry, Manufacturing, and %ontrols, 9n Vitro Release "esting, and 9n Vi!o Bioe ui!alence 7ocumentation#

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

=intments+ creams+ lotions& Minor changes in the ;uantitati)e content of currentl* used e(cipients. Bor detailed guidance on what constitutes a minor or maNor change to ointments and creams see the A' BDA guidelines& Guidance for 9ndustry 4 Nonsterile *emisolid 7osage Forms, *cale4u- and 1osta--ro!al %hangesC %hemistry, Manufacturing, and %ontrols, 9n Vitro Release "esting, and 9n Vi!o Bioe ui!alence 7ocumentation =ral 0i;uids& i# Minor changes to the nature or ;uantit* of e(cipients in simple a;ueous solutions+ particularl* where e)idence is pro)ided to show that the osmolalit* has not been significantl* affected ii# Minor ;uantitati)e changes to currentl* used e(cipients in a;ueous suspensions where e)idence regarding particle si/e and pol*morphism is pro)ided. 'ee Kmoulded suppositories and pessariesL abo)e. A;ueous solutions for inNection& Addition or deletion of up to !@ ben/*l alcohol. =ther minor reformulations and minor changes to the manufacturing procedure+ where it can be con)incingl* argued that the change will not affect bioa)ailabilit* and where rele)ant+ the dissolution profiles in !itro under the same test conditions are e;ui)alent. =ther changes to manufacturing unli8el* to affect bioa)ailabilit*. Bor alread* appro)ed products+ notifications to change the site of manufacture+ method of manufacture+ manufacturing e;uipment or source of acti)e ingredients do not usuall* re;uire bioa)ailabilit* data or a Nustification for the lac8 of bioa)ailabilit* data. <owe)er+ the following applies&

i#

ii#

>)idence should normall* be pro)ided that the dissolution profile is in the same range as pre)iousl* for all solid dosage forms e.g. tablets+ capsules+ suppositories+ pessaries+ implants# and all modified release dosage forms administered b* whate)er route e.g. oral+ transdermal+ )aginal#. Bor semi3solid and li;uid products e.g. ointments+ creams+ lotions+ moulded suppositories+ pessaries#+ e)idence regarding particle si/e and pol*morphism is re;uired see Kmoulded suppositories and pessariesL abo)e#.

Medsafe ma* as8 for additional information in certain cases+ such as a maNor change in a method of manufacture for a modified release product. Changes to the s*nthetic route for an acti)e substance do not re;uire further bioe;ui)alence testing unless the last stage of the s*nthesis and purification are changed. Burther information on the technical re;uirements for bioe;ui)alence testing can be found in 'ections !9 and !7.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

1505

&nterchangea*ility of Multi=source Medicines

Medsafe maintains and publishes a list of Interchangeable Multi3source Medicines IMM#. The list is a)ailable on Medsafe-s web site. Two products are considered to be interchangeable if the* meet the following criteria& 4ither a# the* are pharmaceuticall* e;ui)alent+ and b# their bioa)ailabilities rates and e(tent of absorption# after administration in the same molar dose are similar to such a degree that safet* and efficac* are essentiall* the same. 5r a# the* are pharmaceuticall* e;ui)alent+ and b# the* present no 8nown or potential problems of bio3ine;ui)alence+ and c# the* meet a rele)ant in !itro standard. In most cases products listed as interchangeable are identical dose forms. <owe)er+ in general+ tablets and capsules are clinically e;ui)alent dose forms. Therefore+ where the criteria of bioe;ui)alence are met and interchange would not result in an* clinical problems+ tablets ma* be listed as interchangeable with capsules or !ice !ersa#. All new multi3source medicines are considered for interchangeabilit* with the New ,ealand Reference Product see 'ection !4.4.%# during the e)aluation process. If the* meet the re;uired criteria+ the* are added to the list of interchangeable medicines. ?here consent has alread* been granted for a multi3source medicine that is not alread* on the IMM list+ the sponsor ma* submit a re;uest for listing using the CMN form and pro)ide the appropriate bioe;ui)alence data and fee.

150501

'tyle and content of the &nterchangea*le Multi=source Medicine ist

The original IMM list published in !""4 as a boo8let was based on wor8 e)aluating the interchangeabilit* of the top %22 medicines sold in New ,ealand at that time. 'ince !""4 the list has been graduall* e(panding to include all medicines for which there is a multi3source )ersion appro)ed for sale in New ,ealand. In the past Medsafe has onl* published interchangeable medicines in this boo8let. ?ith the current interest in substitution at pharmac* le)el+ it seemed opportune to reinforce which medicines are not considered interchangeable in the %222 edition and subse;uent editions of the IMM 0ist. ?here a medicine is considered interchangeable with the reference product+ it is included in 'ection ! of the list. If it is not interchangeable+ the medicine is published as such in the New Zealand Ga)ette and is now listed in 'ection % of the IMM list. >ach section is further di)ided into two parts as follows.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

'E(#&$N 1: &nterchangea*le multi=source medicines


Medicines which either pose no ris8 8nown or theoretical# of bio3ine;ui)alence 'ection !.!# or ha)e been pro)en to be bioe;ui)alent to an appropriate reference product 'ection !.%#.

+ection 101 "edicines that pose no risk of ,io8ine9uivalence


Man* o)er3the3counter =TC# products+ including nasal spra*s+ are included in 'ection !.!+ along with medicines such as oral solutions and a;ueous inNections. Medicines in this section are assessed for safet* ;ualit* and efficac* b* Medsafe before the* can be sold in New ,ealand and an* product included in this section can be considered interchangeable with an* pharmaceuticall* e;ui)alent medicine. A bioe;ui)alence stud* is not re;uired as part of the application to Medsafe. The following groups of medicines are considered interchangeable& All pharmaceuticall* e;ui)alent restricted medicines+ pharmac*3onl* medicines+ and general sale medicines all dose forms# All pharmaceuticall* e;ui)alent prescription medicines+ or controlled drugs re;uiring a prescription+ in the following dose forms& oral solutions and powders for reconstitution for oral solutions a;ueous inNections and irrigations+ and powder for reconstitution for a;ueous inNections pure substances e.g. )olatile li;uids used as anaesthetics# nebuliser solutions

$hy are some 5-. medicines not included in Section 6267 Bor a small number of =TC products+ e.g. isosorbide mononitrate# bio3ine;ui)alence could produce serious medical conse;uences. In these instances+ Medsafe re;uires a bioe;ui)alence stud* to be submitted with the application. Depending on the result of the e)aluation+ the product will be listed as ha)ing been pro)en to be interchangeable 'ection !.%# or not interchangeable 'ection %#.

+ection 102

"edicines that have proven ,ioe9uivalent to a NZ Reference Product

All medicines listed in 'ection !.% are prescription medicines+ or controlled drugs that re;uire a prescription+ which are li8el* to be associated with clinical conse;uences if bioe;ui)alence is not demonstrated. Medsafe re;uires that the bioe;ui)alence stud* submitted for e)aluation pro)e that the multi3source product is in the same dosage and ph*sico3chemical form as the reference product i.e. pharmaceuticall* e;ui)alent#+ and is bioe;ui)alent with the reference product before the product can enter the N, mar8et. Medicines are listed alphabeticall* b* acti)e ingredient s# name and are interchangeable at pharmac* le)el without compromising clinical outcome. Products are identified with the name of the distributor rather than the name of the manufacturer since this is the information that most clearl* identifies the medicine for a prescriber or pharmacist using the list. $hy are some 5-. acti!e ingredients listed in Section 6287 Medicines ma* contain an acti)e ingredient which is classified in both prescription and =TC categories+ howe)er the indications for the different classifications are usuall* ;uite different. Medsafe re;uires products to demonstrate bioe;ui)alence for the prescription formulations and indications. The =TC indications are usuall* for the treatment of minor+ self3limiting conditions for which the clinical conse;uences of bio3ine;ui)alence are minimal. $hy are some products which meet the criteria of Section 826 listed in Section 6287 In some circumstances a prescription medicine+ or a controlled drug that re;uires a prescription+ is co3 mar8eted b* two companies. In such cases the products ha)e identical formulations and dose forms and

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

are therefore interchangeable e)en if the* meet the criteria listed for non3interchangeabilit* listed in 'ection %.

'E(#&$N +: Medicines considered to *e non=interchangea*le


Medicines which are either generall* considered to be non3interchangeable on pharmacological grounds 'ection %.!# or which fall outside of Medsafe-s bioe;ui)alence guidelines+ and ha)e been ga/etted as non3interchangeable 'ection %.%# are listed in these sections.

+ection 201 "edicines generally considered to ,e non8interchangea,le


?hile prescription medicines+ and controlled drugs that re;uire a prescription+ listed in this section ha)e met Medsafe-s re;uirements for entr* to the mar8et+ the* are not considered to be interchangeable owing to a number of pharmacological and pharmaceutical reasons including& a# the product has a narrow therapeutic inde ()-1)2 In cases where the margin between therapeutic and to(ic effects is )er* small+ i.e. an NTI+ the differences in bioa)ailabilit* between the reference and multi3source product permitted in bioe;ui)alence testing ma* gi)e rise to significant clinical conse;uences. Products with an NTI+ such as anticon)ulsants+ antiarrh*thmics+ theoph*lline+ warfarin+ isotretinoin+ c*closporin+ th*ro(ine+ etc. are+ therefore+ not usuall* considered to be interchangeable. b# the deli!ery systems or dose forms of the products are not pharmaceutically e9ui!alent2 Transdermal patches+ s*stemicall* acting creams or ointments+ or suppositories ma* ha)e been supported b* data demonstrating bioe;ui)alence with oral+ or other dose forms+ as e)idence of efficac*. The differences in pharmaceutical form+ howe)er+ mean that the products are not considered to be interchangeable. c# there is no acceptable method to establish bioe9ui!alence e.g. some topical or locall* acting medicines. In most circumstances products in this categor* must demonstrate efficac* on the basis of clinical trials data+ and interchangeabilit* with another product cannot be assessed. Multi3source nasal spra*s mar8eted as prescription medicines+ howe)er+ are an e(ception to this rule. Nasal spra*s are appro)ed for mar8eting when the* meet appropriate pharmacopoeial standards and the maNorit* of the dose is li8el* to be deposited at the re;uired site. As the deli)er* de)ice can ha)e a large effect on the amount of dose deli)ered to the site of action+ Medsafe cannot ma8e an* statement about the interchangeabilit* of different nasal spra*s with the same acti)e ingredients unless the* ha)e been shown to meet an appropriate bioe;ui)alence standard. Note: ?here there is an acceptable method of establishing bioe;ui)alence+ such as s8in blanching tests for topical steroid preparations+ or comparati)e clinical trial data ha)e been submitted+ the product will be listed in 'ection !.%. All =TC nasal spra*s are considered interchangeable as the* pose no ris8 of bio3ine;ui)alence#.

+ection 202 "edicines ga:etted as non8interchangea,le


In a small number of circumstances Medsafe ma* ga/ette a medicine as non3interchangeable. This ma* occur where the sponsor for a multi3source product has pro)ided clinical trial data as e)idence of efficac*+ and so no assessment of interchangeabilit* is possible. Alternati)el*+ the bioe;ui)alence stud* pro)ided in the application ma* fail to meet the international bioe;ui)alence criteria administered b* Medsafe+ b* demonstrating that the multi3source medicine is more bioa)ailable than the comparator reference product. In such cases Medsafe liaises with its e(pert committee to assess whether the increased bioa)ailabilit* is li8el* to cause an* significant difference in the benefit&ris8 profile of the multi3source product compared to the inno)ator. If no difference in benefit&ris8 is e(pected+ and the multi3source product meets all of Medsafe-s other safet* and ;ualit* criteria+ the product ma* be accepted as ha)ing been

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

pro)en to be safe and effecti)e. It ma* then be appro)ed for distribution in New ,ealand but ga/etted as non3interchangeable. This polic* recognises the limitations of bioe;ui)alence studies and the fact that Kbioe;ui)alenceL means that on a)erage two products can be e(pected to beha)e the same wa*+ but in some patients there ma* be significant differences resulting in serious clinical conse;uences. Non3interchangeabilit* in New ,ealand does not mean that the generic medicine is inherentl* ineffecti)e or defecti)e. Instead+ it means that+ as a precaution+ a patient should be prescribed one brand or the other and+ if the medicine has satisfactor* results at the prescribed dose+ the patient should be maintained on the same brand and not switched bac8 and forth between brands from prescription to prescription. ?here a product fails a bioe;ui)alence test because it has decreased bioa)ailabilit* compared to the inno)ator+ the product ma* onl* be appro)ed on the basis of further clinical trial data. This approach to the e)aluation of multi3source medicines has been in place since the !""! re)iew of Medsafe-s e)aluation procedures.

15050+

New Zealand reference )roduct

The New ,ealand Reference Product N,RP# is normall* the inno)ator product+ but where the inno)ator is not on the mar8et in New ,ealand+ the N,RP is the mar8et leader. A product is not included in the list as a N,RP until there is a multi3source product on the mar8et in New ,ealand for which bioe;ui)alence with that reference product has been established. It is possible to ha)e more than one N,RP for a particular medicine e.g. where more than one product has entered the mar8et through pro)ision of clinical trial data as e)idence of clinical efficac*. In this situation+ a new multi3source medicine ma* use either of the N,RPs as the comparator product for a bioe;ui)alence stud*+ and would be listed as interchangeable onl* with the reference product with which it was compared in the stud*.

150503

Maintenance of the &nterchangea*le Multi=source Medicine ist

In the past+ once a multi3source medicine has been ga/etted+ the sponsor compan* has been sent a letter informing it of the proposed entr* on the IMM list and as8ing it to notif* Medsafe when the product is mar8eted in New ,ealand. =nce confirmation has been recei)ed that the product is on the mar8et+ an entr* for the product has been included in the web site and published in the subse;uent monthl* Med3 safety e3mail. ?hen distribution of a product on the IMM list was discontinued+ the entr* for that product was amended to show the discontinuation. The entr* remained in the list for two *ears to allow remaining stoc8s held in pharmacies to be dispensed. Two *ears after the date of discontinuation of the product+ the entr* as deleted from the list. In future+ Medsafe intends to adopt a different process. It will place products on the list as soon as the* are appro)ed for distribution in New ,ealand rather than wait for companies to ad)ise that mar8eting has commenced. Medsafe appreciates that the dela* in mar8eting ma* sometimes be due to patent considerations+ howe)er+ it is not in a position to 8now when patents are e(piring and so must rel* on the industr* to deal with patent issues. Medsafe will also lea)e products on the list until their sponsors formall* ad)ise that mar8eting has permanentl* ceased+ or until registration has lapsed for some reason. ?hile this will mean that some products listed ma* not actuall* be a)ailable on the mar8et when the* first appear on the list+ the change in procedure will ma8e the list much easier and ;uic8er to compile+ publish and maintain.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

'ection 18:

Fioe?ui.alence #esting of $ral Medicines

Section summary "his section descri+es the re uirements for designing and conducting a +ioe ui!alence study in!ol!ing oral ta+lets, ca-sules and sus-ensions, and for analysing and inter-reting the results

1801

&ntroduction

'e)eral maNor regulator* authorities o)erseas ha)e produced guidelines for establishing bioe;ui)alence. These guidelines describe+ in )ar*ing degrees of detail+ the principles in)ol)ed in the design and conduct of bioe;ui)alence trials+ and the anal*sis of the data. The* are continuall* being updated as e(perience and 8nowledge on bioe;ui)alence grows. Despite considerable international agreement on the general principles of bioe;ui)alence and its establishment+ there are differences of opinion regarding some aspects of how some bioe;ui)alence studies should be conducted and how data should be e)aluated. This New ,ealand guideline for bioe;ui)alence testing is largel* based on the guidelines listed below and what Medsafe regards as best current international practice. The e)idence re;uired for bioe;ui)alence usuall* consists of comparati)e bioa)ailabilit* data. In some e(ceptional cases other data e.g. in !itro dissolution# ma* be sufficient+ or the formulation ma* be such that no comparati)e testing is necessar*. 'ituations where comparati)e bioa)ailabilit* studies are and are not necessar*+ and the choice of acceptable reference products for bioe;ui)alence studies+ are outlined in 'ection !4.

180+

&m)ortant $.erseas Fioe?ui.alence Guidelines

The following o)erseas guidelines ha)e been used as the basis for the New ,ealand guideline. Euro)ean (ommission Rules Go.erning Medicinal 6roducts in the Euro)ean (ommunity Volume &&& and (6M6 Notes for Guidance 1harmaco3inetic studies in man. 9n!estigation of +ioa!aila+ility and +ioe ui!alence# %linical testing of -rolonged action forms with s-ecial reference to e>tended release forms . Juality of -rolonged release oral solid dosage forms# :nalytical !alidation. "nited 'tates Food and !rug Administration -F!A/ The Anited 'tates BDA guidelines ha)e been published as two KGeneral InformationL chapters in the Anited 'tates Pharmacopoeia YYIII+ !""9& T!266] 9n !itro and 9n !i!o /!aluation of 7osage Forms+ A'P YYIII+ !""9+ p !"%4. T!2"2] 9n !i!o Bioe ui!alence Guidelines+ A'P YYIII+ 'e)enth 'upplement+ !""5+ page 42%%.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

Australian #hera)eutic Goods Administration -#GA/ :ustralian Guidelines for the Registration of 7rugs, $olume !+ Pul* !""4+ Appendi( %%1#. #hera)eutic 6roducts !irectorate> 7ealth 6roduct and Food Franch> 7ealth (anada %onduct and :nalysis of Bioa!aila+ility and Bioe ui!alence *tudies 4 1art :C ,ral 7osage Formulations used for *ystemic /ffects !""%#F and %onduct and :nalysis of Bioa!aila+ility and Bioe ui!alence *tudies 4 1art BC ,ral Modified Release Formulations !""5#. World 7ealth $rganisation -W7$/ 9nterchangea+le multi4source -harmaceutical -roductsC Multi4source AgenericB -harmaceutical -roductsC Guideline on registration re uirements to esta+lish interchangea+ility in ?<= Technical Report 'eries 67:+ !""7+ Anne( ".

1803

!efinitions

2ioa&aila1ilit! is a measure of the rate and e(tent of absorption of the pharmacologicall* acti)e form or forms of the acti)e ingredient from a medicine+ as reflected b* the time3concentration cur)e in the s*stemic circulation or b* its e(cretion in urine. In addition to the e(tent of absorption+ the rate of absorption ma* be important for man* medicines+ e.g. if a rapid effect is needed or if therapeutic efficac* depends on attaining a certain pea8 concentration. Rapid absorption ma*+ howe)er+ lead to transient side effects or serious to(icit* for medicines with a narrow therapeutic inde(. In some circumstances+ determining the amount e(creted or measuring an appropriate pharmacod*namic effect ma* be the onl* a)ailable method of gauging bioa)ailabilit* or bioe;ui)alence. Bactors affecting bioa)ailabilit* include the ph*sico3chemical characteristics of the acti)e ingredient s# e.g. lipid.water solubilit*+ stabilit* in an acid medium+ salt form+ particle si/e#+ the nature and ;uantities of e(cipients+ t*pe of formulation enteric coated+ sustained release etc.# and the e(tent of first pass metabolism b* the gut and li)er. Patient factors include the timing of the dose in relation to eating+ interactions with other medicines ta8en concurrentl*+ gastrointestinal motilit* and concurrent disease states. 2ioe*ui&alence is a comparati)e term. Pharmaceuticall* e;ui)alent medicines are assumed to be bioe;ui)alent if their bioa)ailabilities rate and e(tent of absorption in the s*stemic circulation after administration# are so closel* comparable that their therapeutic effect+ with respect to efficac* and safet*+ will be essentiall* the same. ?hether differences in bioa)ailabilit* between different dose forms+ multi3source medicines and reformulations of a dosage form will result in significant differences in clinical effects depends on the nature of the medicine and the mode of its use. Bor e(ample+ ;uite small differences in bioa)ailabilit* can lead to serious complications with medicines such as digo(in and ;uinidine which ha)e low therapeutic indices. Bor other medicines e.g. ben/odia/epines used for their h*pnotic or anti3an(iet* properties# differences in bioa)ailabilit* ha)e to be greater in order to produce clear e)idence of lac8 of efficac* or undesirable effects. 'ince it is impossible to formulate uni)ersall* applicable rules for bioe;ui)alence+ each product needs to be considered indi)iduall*. As a general principle+ two products ma* be said to be bioe;ui)alent if the "2@ confidence inter)als for their mean Cma(+ Tma(+ and AAC from /ero time to infinit* for single doses or within a dosing inter)al at stead* state# are within `%2@.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

The usuall* accepted criteria for concluding bioe;ui)alence based on a difference of not more than %2@# are that the "2@ confidence inter)als for the ratio between the test and reference geometric means for AAC and Cma( determined using log3transformed data# lie wholl* within the range of 2.62 to !.%9 and the non3parametric "2@ confidence inter)al for the difference in T ma( between the formulations lies within a clinicall* acceptable range. ?here close dosage control is critical+ a %2@ )ariation in the rate and e(tent of absorption ma* be considered too wide. Tighter limits for permissible differences in bioa)ailabilit* ma* be re;uired for medicines that ha)e& !. %. :. 4. a narrow therapeutic inde( serious+ dose3related to(icit* a steep dose.effect cur)e+ or non3linear pharmaco8inetics within the therapeutic dosage range.

?here an applicant considers a )ariation in the rate or e(tent of absorption greater than `%2@ is acceptable+ this must be e(plained and Nustified in the application dossier. The allowable limit will depend upon clinical considerations Supra1ioa&aila1ilit! is the term used when a multi3source product displa*s a bioa)ailabilit* appreciabl* larger than the reference product. ?hen this occurs+ reformulation and a final comparati)e bioa)ailabilit* stud* will be necessar*. =therwise+ clinical trial data as re;uired for a new chemical entit* will be re;uired to support the application for the proposed formulation.

1805

Varia*les in a (om)arati.e Fioa.aila*ility 'tudy

The blood plasma or serum concentration3time cur)e of the pharmacologicall* acti)e substance s# compared to a reference formulation pro)ides the best measure of bioa)ailabilit* for medicines with a s*stemic effect. ?here the parent drug substance is an acti)e form and one or more of its metabolites are also acti)e+ contribution of the metabolite s# to the total pharmacological response should be considered in determining whether the metabolite should be measured as well as the parent compound. ?here it is not possible or fa)ourable to measure the acti)e substance s# in serum or plasma+ other less direct measures will be necessar*. These could include determining the ;uantit* of the acti)e substance or its metabolites e(creted in urine+ or measuring pharmacod*namic )ariables. If data based on measurements other than blood concentrations are presented e.g. sali)a or urine concentrations#+ their rele)ance must be demonstrated. Asuall* the ;uantification of pharmacod*namic parameters is less e(act than the determination of concentrations of drug substances and metabolites in bod* fluids. Bor medicines that are mi(tures of geometric isomers e.g. clomiphene#+ both isomers should normall* be assa*ed.

180501

E1tent of a*sor)tion

The e(tent of absorption is the fraction of the dose which enters the s*stemic circulation+ as estimated using the ^area under the cur)e^ AAC# of plasma concentration )ersus time. >(tent of absorption can also be estimated from the fraction of the dose e(creted in urine as the acti)e form and.or its metabolites.

18050+

Rate of a*sor)tion

The rate of absorption determines the time dela* between administration of a medicine and the time of the ma(imum pea8# concentration in the fluid being assa*ed+ usuall* plasma. The rate of absorption can influence the amount of medicine reaching the s*stemic circulation in the case of a medicine with non3linear 8inetics+ for e(ample where there is saturable first3pass metabolism.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

=ther parameters that might pro)ide a better estimate of the rate of absorption e.g. the time to reach a particular concentration or fraction of C ma(# ma* be used where appropriate. The use of these parameters must be Nustified in the dossier.

180503

6harmacodynamic res)onses

?here a suitable method for assa*ing the acti)e form s# in bod* fluids is not a)ailable+ it ma* be possible to obtain an indirect indication of bioa)ailabilit* or bioe;ui)alence b* repeated determinations of pharmacod*namic or biochemical responses following administration of a medicine. 'ome pharmacod*namic )ariables respond rapidl* to a medicine and are easil* and accuratel* measured e.g. heart rate#. <owe)er+ since there is a comple( relationship between the onset+ intensit* and duration of the response and the concentration3time cur)e of the medicine and.or its metabolites in biological fluids+ these )ariables ma* not be ideal. In addition+ pharmacod*namic measurements ma* not be sufficientl* precise to detect significant differences in bioa)ailabilit*. Bor these reasons+ bioa)ailabilit*.bioe;ui)alence studies based on chemical assa*s of the acti)e form s# are preferred. If pharmacod*namic data onl* are pro)ided+ the applicant should outline which other methods were tried and the reasons wh* the* were unsuitable. The following re;uirements should be recognised when planning+ conducting and assessing the results of a stud* intended to demonstrate e;ui)alence b* measuring pharmacod*namic responses to a medicine& The response which is measured should be a pharmacological or therapeutic effect which is rele)ant to the claims of efficac* and.or safet*. The methodolog* should be )alidated for precision+ accurac*+ reproducibilit* and specificit*. Neither the test formulation nor the reference product should produce a ma(imal response in the course of the stud*+ since it ma* be impossible to distinguish differences between formulations gi)en in doses which gi)e ma(imum or near3ma(imum effects. In)estigating dose3response relationships ma* be necessar*. The response should be measured ;uantitati)el* under double3blind conditions and be recorded in a machine3produced or machine3recorded fashion on a repetiti)e basis to pro)ide a record of the pharmacod*namic e)ents which are substitutes for plasma concentrations. If such measurements are not possible+ recordings on )isual analog scales ma* be used. ?here data are limited to ;ualitati)e categorised# measurements+ appropriate special statistical anal*ses will be re;uired. Non3responders should be e(cluded from the stud* b* prior screening. The criteria b* which responders )ersus non3responders are identified should be stated in the protocol. ?here an important placebo effect can occur+ comparison between products can onl* be made b* a -riori consideration of the placebo effect in the stud* design. This ma* be achie)ed b* adding a third phase+ with placebo treatment+ in the design of the stud*. A cross3o)er design should normall* be used where appropriate+ but where a cross3o)er design is inappropriate+ a parallel group stud* design should be chosen. The underl*ing patholog* and natural histor* of the condition should be considered in the stud* design. There should be 8nowledge of the reproducibilit* of the base3line conditions. In studies where continuous )ariables could be recorded+ the time course of the intensit* of the drug action can be described in the same wa* as in a stud* in which plasma concentrations are measured. Brom this+ parameters can be deri)ed which describe the area under the effect3time cur)e+ the ma(imum response and the time when ma(imum response occurred. 'tatistical considerations for the assessment of the outcome of the stud* are+ in principle+ the same as for bioe;ui)alence studies using plasma concentrations. <owe)er+ a correction for the potential non3linearit* of the relationship between the dose and the area under the effect3time cur)e should be made+ on the basis of the outcome of the dose ranging stud*.

!:7

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

The con)entional acceptance range+ as applied for bioe;ui)alence+ is not appropriate in most cases. It should be defined on a case3b*3case basis and described in the protocol.

180505

(om)arati.e in vitro dissolution rate

If it can be demonstrated that there is no suitable ethicall* acceptable in !i!o method of establishing bioe;ui)alence+ and that such a method cannot be de)eloped+ appropriate comparati)e in !itro dissolution data ma* be an acceptable substitute. Dissolution studies should possess suitable discriminator* power and be carried out at :5VC and ph*siologicall* meaningful p<s. More than one batch of each formulation should be tested. Comparati)e dissolution profiles+ rather than single point dissolution test data+ should be generated. The design should include& Indi)iduall* testing at least si( dosage units e.g. tablets+ capsules# of each batch. Mean and indi)idual results should be reported along with their standard de)iations or standard errors. Measuring the percentage of nominal content released at a number of suitabl* spaced time points to pro)ide a profile for each batch+ e.g. at !2+ %2 and :2 minutes or as appropriate to achie)e )irtuall* complete dissolution. Conducting the tests on each batch using the same apparatus and+ if possible+ on the same or consecuti)e da*s. Binal specifications for routine dissolution testing of the test product should be based on the data generated in this comparati)e stud* used to support e;ui)alence of the test and reference products.

1808

!esigning a (om)arati.e Fioa.aila*ility 'tudy

Good trial design is essential. In)estigators should consider what is alread* 8nown about the nature and pharmaco8inetics of the test medicine. ?hen published data are not a)ailable+ a pilot stud* ma* be necessar* to ascertain& the li8el* T ma( and Cma( so that the final design will pro)ide a sufficient number of samples around Tma( to characterise this parameter and C ma( ade;uatel* the sampling times+ in single dose studies+ needed to characterise the terminal elimination rate constant and the AAC from the last data point to infinit* the ade;uac* of the assa* sensiti)it* and precision at the intended dose+ and the )ariance in Cma( and AAC to allow estimation of the number of subNects re;uired to achie)e appropriate statistical power The stud* should be a balanced cross3o)er design with appropriate randomisation of the subNects to the different treatment se;uences+ unless the nature of the medicine means that a return to baseline )alues is not e(pected within a reasonable washout period between trial phases. Parallel group design ma* be suitable+ but is often a)oided because of the need to increase the number of subNects. The use of a cross3o)er design does run the ris8 of se;uence effects+ but if the stud* is appropriatel* designed se;uence effects are not usuall* a problem.

180801

'ingle dose .ersus steady=state studies

'ingle dose studies are appropriate in the maNorit* of cases. A stead*3state stud* ma* be appropriate in the following circumstances& ?here the medicine has a long terminal elimination half3life and blood concentrations after a single dose cannot be followed for sufficient time. ?here assa* sensiti)it* is insufficient to follow the terminal elimination phase for an ade;uate period of time.

!:5

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

Bor medicines which are so to(ic that+ ethicall*+ the* can onl* be administered to patients for whom the* are a necessar* part of therap*+ but where multiple dose therap* is re;uired+ e.g. man* c*toto(ics. Bor modified3release products where it is necessar* to assess the fluctuation in plasma concentration o)er a dosage inter)al at stead* state. Bor those medicines which induce their own metabolism or show large intra3indi)idual )ariabilit*. Bor enteric3coated preparations where the coating is inno)ati)e. Bor enteric coated preparations+ for which the release characteristics ha)e been pre)iousl* established+ a stead*3state stud* is not alwa*s re;uired. Bor combination products where the ratio of plasma concentration of the indi)idual substances is important. Bor medicines that e(hibit non3linear i.e. dose3 or time3dependent# pharmaco38inetics. ?here the medicine is li8el* to accumulate in the bod*. In stead* state studies+ the administration scheme should follow the usual dosage recommendation.

18080+

6arameters

The parameters that should be determined in a bioa)ailabilit* stud* include& ma(imum medicine concentration Cma(#F time ta8en to reach the ma(imum concentration Tma(# area under the medicine concentration time cur)e AAC# terminal elimination rate constant 8el#+ and others as appropriate These parameters should be calculated using the original concentration )s. time data rather than b* cur)e fitting methods based on compartmental models. Bor modified3release products gi)en as a single dose+ absorption rate plots should be prepared.

180803

(hoice of su*Jects

To reduce )ariabilit* caused b* disease+ bioa)ailabilit* studies are usuall* carried out in adult human )olunteers of both genders where appropriate# who are in good health+ of a)erage weight e.g. within !9@ of their ideal weight as gi)en in the current Metro-olitan =ife 9nsurance %om-any (eight and Mass "a+les# and in the age range prior to the onset of age3related ph*siological changes usuall* !63 72 *ears of age#. The super)isor* ph*sician should initiall* obtain a comprehensi)e recent medicine histor* including alcohol inta8e+ smo8ing and use of oral contracepti)e tablets# to e(clude possible interference with assa*s+ effects on pharmaco8inetics+ pharmacological interactions and ad)erse reactions such as h*persensiti)it*. As well+ the ph*sician should conduct a medical e(amination and test li)er+ 8idne* and haematological function. Ps*chological characteristics should also be assessed to e(clude subNects unli8el* to compl* with stud* restrictions and.or unli8el* to complete the stud*. During the stud*+ the health of the subNects should be regularl* monitored so that the onset of side effects+ to(icit*+ or an* intercurrent disease ma* be recorded and appropriate measures ta8en. Preferabl* both genders should be included in the stud*. <owe)er+ the choice of gender must be consistent with usage and safet* criteria. ?omen should be re;uired to gi)e assurance that the* are not pregnant+ nor li8el* to become pregnant until after the stud*. This should be confirmed b* a pregnanc* test immediatel* prior to the first and last dose of the stud*.

!:6

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

Bor a medicine representing a potential ha/ard in one group of users+ the choice of subNects ma* need to be narrowed+ e.g. studies on teratogenic medicines should be conducted in males. ?here the ris8 of side effects or to(icit* is significant+ studies ma* ha)e to be carried out in patients who are being treated with the test medicine but whose disease state is stable.

180805

'tandardisation of e1)erimental conditions

Bor medicines ta8en orall*+ gastrointestinal conditions should be standardised. 'ubNects should be fasted for at least !2 hours before and %34 hours after dosing+ or if more appropriate for the medicine concerned# the dose should be gi)en with or before.after a standardised meal. Meals consumed after dosing and during the blood3sampling period should be standardised and ta8en at standardised times after the dose. An* fluids ta8en with the dose should be the same for all subNects. 'tandardisation of posture and ph*sical acti)it* is important to minimise )ariation in li)er blood flow+ especiall* for high clearance medicines+ and should approach the conditions li8el* to be encountered in clinical use. Posture ma* also affect gastric empt*ing rates. Therefore+ subNects should not be allowed to recline until at least two hours after oral administration of the medicine. The times at which samples are ta8en should be similar in all subNects.

180808

Num*er of su*Jects

The minimum acceptable number of subNects ma* be as low as !%+ howe)er+ the number should be sufficient+ in the case of confidence inter)als+ to gi)e precise estimates of the target parameters and+ in the case of h*pothesis testing+ sufficient to pro)ide the necessar* discriminator* power normall* 62@# to detect the ma(imum allowable difference usuall* `%2@# in C ma(+ AAC etc. This number+ ^n^+ ma* in man* cases be estimated in ad)ance using means+ standard de)iations and sample si/es from published or pilot data. The calculation formula depends on the statistical method to be used in the anal*sis of the results at the completion of the stud*. Computation methods are outlined in 'ection !9.!2. The number of subNects recruited should be sufficient to allow for possible withdrawals or remo)als from the stud*. Reasons for an* withdrawals e.g. ad)erse reactions# should be reported and the subNect-s plasma.serum.blood le)el data pro)ided. It is acceptable to replace a subNect withdrawn from the stud*+ once it has begun+ pro)ided the substitute follows the same protocol originall* intended for the withdrawn subNect. If the calculated number of subNects appears to be higher than is ethicall* Nustifiable+ it ma* be necessar* to accept a statistical power which is less than desirable. Normall* it is not practical to use more than about 42 subNects in a bioa)ailabilit* stud*. ?here calculations suggest that an e(cessi)e number of subNects is re;uired+ clinical efficac* and.or safet* studies are an alternati)e. The use of a co3administered acti)e ingredient labelled with non3radioacti)e isotope as a reference+ or studies in which treatments are replicated within each subNect+ ma* impro)e discriminator* power for highl* )ariable medicines. 'e;uential testing ma* also be acceptable for studies e(pected to re;uire a large number of subNects+ i.e. a stud* is conducted on a predetermined subset of the re;uired sample and the intended statistical anal*sis is performed. If the acceptance criteria are met+ no further subNects need to be tested. If the acceptance criteria are not met+ the results from the first part of the stud* can be used to determine how man* more subNects should be tested. Appropriate statistical tests e.g. se;uential t3test# which ma8e allowance for this design should be used. The ethicall* Nustifiable ma(imum number of subNects should also be considered. The final statistical anal*sis then uses all of the data.

180809

Formulation and ?uality control data re?uirements !:"

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

The detailed formulation of the test medicine used should be pro)ided+ or otherwise declared to be identical to that intended for mar8eting. Bor tablets and capsules the test formulation used should originate from either a production3run batch or a pilot3scale batch of at least !2@ of the full production scale or !22+222 units+ whiche)er is the greater+ and manufactured using full production3scale e;uipment+ unless otherwise Nustified. In the case of a production batch being less than !22+222 units+ the sample should originate from a full production batch. Bor suspensions the test formulation used should originate from either a production3run batch or a pilot3scale batch of at least !2@ of the full production scale and manufactured using full production3 scale e;uipment+ unless otherwise Nustified. All medicines used in bioe;ui)alence studies should be manufactured in accordance with good manufacturing practice GMP#. Hualit* control data should be pro)ided for both the test and reference products used in the trial. The minimum data re;uired is the batch number+ date and scale of manufacture+ mean potenc*+ uniformit* of potenc* as determined b* assa*ing !2 indi)idual dosage units and+ for tablets and capsules+ disintegration time and dissolution profiles determined in a;ueous media using standard 1P+ Ph >ur or A'P e;uipment and procedures. Alternati)el*+ other full* )alidated dissolution procedures ma* be used. Note that an* final specifications for in !itro dissolution of the multi3source product should be deri)ed from the dissolution profiles for the batch that was found to be bioe;ui)alent to the reference product. The mean potencies of the test and reference product should not differ b* more than 9@.

18080:

Num*er and timing of sam)les

The number t*picall* !%3!6 blood samples per dose# and timing of samples should be sufficient to enable reasonabl* accurate estimates of C ma( and Tma(+ and accurate estimates of AAC and the elimination rate. This information ma* be obtained in ad)ance from literature data or a pilot stud*. The blood sampling period in trials using a single dose of a prompt3release product should e(tend to at least three elimination half3li)es in the terminal elimination phase. 'ampling should be continued for a sufficient period to ensure that the area e(trapolated from the time of the last measured concentration to infinite time is onl* a small percentage normall* less than %2@# of the total AAC. The use of truncated AACs+ i.e. AACt+ is undesirable but it ma* be una)oidable in certain circumstances such as in the presence of enterohepatic rec*cling where the terminal elimination rate constant cannot be calculated accuratel*. There should be sufficient points on the terminal linear part of the log3concentration )s. time cur)e to calculate the terminal elimination rate constant. The calculation should be based on at least four e(perimental points at appropriate inter)als on the graph. The number of points used to calculate the terminal elimination rate constant should preferabl* be determined b* e*e from a semi3logarithmic plot+ rather than b* allowing a computer program to ma8e the decision. Inter)als between successi)e data points used to calculate the terminal elimination rate constant should+ in general+ not be longer than the half life of the medicine. In stead* state studies+ sampling should be carried out o)er a full %4 hour c*cle so that an* effects of circadian rh*thms ma* be detected+ unless these rh*thms can be argued not to ha)e practical significance.

!42

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

In e(periments re;uiring urine collection+ it is important that subNects be carefull* trained and super)ised to ensure that all urine samples are collected according to the protocol. An* urine not collected will in)alidate this part of the trial and should be ta8en into account during anal*sis of the data. Bor a %4 hour stud*+ sampling times of 23%+ %34+ 436+ 63!%+ !%3%4 hours are usuall* appropriate. ?here urinar* e(cretion is measured in a single3dose stud* it is necessar* to collect urine for se)en or more half3li)es.

18080;

Fasting and non=fasting studies

Generall* a single dose stud* should be conducted after an o)ernight fast of at least !2 hours+ with a subse;uent fast of %34 hours following dose administration. <owe)er+ where the dosage form is a modified release product or when it is recommended that the medicine be gi)en with food+ then the influence of food on the bioa)ailabilit* should be e(amined. The meal should contain appro(imatel* :2342g of fat as this is li8el* to cause ma(imum perturbation to the release and absorption of the medicine. If a recommendation is made about when the medicine should be ta8en in relation to eating e.g. immediatel* before food#+ this should also be ta8en into account in the design. Bed studies are also re;uired when fasted studies ma8e assessment of Cma( and Tma( difficult.

18080<

Medicine administration

The ;uantit*+ t*pe and timing of food and fluid ta8en concurrentl* with the medicine should be stated+ and should be controlled. The time of da* the medicine was ta8en should also be stated+ and whether or not the subNects were ambulator* and for how long. Concurrent use of other medicines+ including oral contracepti)es+ inta8e of alcohol and caffeine+ and smo8ing cigarettes+ should be stated and should be controlled. ?hene)er possible and safe+ and when gi)en b* the same route+ the molar e;ui)alent doses of medicine in the test formulation s# and the reference product should be the same. In studies comparing a modified3release product with a prompt3release product+ it ma* be appropriate for reasons of safet* and comparabilit* of plasma concentrations to gi)e the prompt release product in di)ided doses or as a single+ lower dose. In single dose trials+ a sufficient inter)al should be allowed between the administration of each formulation to ensure that the pre)ious dose of medicine and an* metabolites being measured ha)e been completel* eliminated. Appro(imatel* ten elimination half3li)es of the medicine after the pea8 is usuall* a sufficient inter)al. Consideration will need to be gi)en to e(tending this period if acti)e metabolites with longer half3li)es are produced. In stead*3state trials+ the dosage regimen should be identical to the established dosage regimen of the reference product. 'ampling of blood or urine should be carried out after the plateau stead* state# has been attained. It should be demonstrated that the plateau has been attained. ?ashout of the pre)ious treatment can o)erlap with build3up of the second treatment+ pro)ided the build3up period is sufficientl* long at least three times the dominating half3life#. The pattern of blood or urine collections+ or other sampling procedures+ should be standardised for each subNect. ?here)er possible the trial design should ensure that the order se;uence# of administering medicine treatments to subNects is randomised and balanced.

1809

Modified=release 6roducts

!4!

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

This section refers to orall* administered modified3release MR# dosage forms of medicines which do not ha)e complicated characteristics.

180901

(haracteristics

A modified3release dosage form is defined as one for which the medicine3release characteristics of time course and.or medicine3release location are chosen to accomplish therapeutic or con)enience obNecti)es not offered b* prompt3release dosage forms. Bor the purpose of these guidelines+ these include& dela*ed release sustained release mi(ed immediate and sustained release mi(ed dela*ed and sustained release mi(ed immediate and dela*ed release Generall*+ these products should& act as modified3release formulations and meet the claims made b* the applicantF preclude the possibilit* of an* dose dumping effectF pro)ide a therapeutic performance comparable to the reference prompt3release formulation administered b* the same route in multiple doses of an e;ui)alent dail* amount# or to the reference modified3release formulationF produce consistent pharmaco8inetic performance between indi)idual dosage unitsF and produce plasma le)els which lie within the therapeutic range where appropriate# for the proposed dosing inter)als at stead* state. If all of the abo)e conditions are not met but the applicant considers the formulation to be acceptable+ a case to this effect should be pro)ided.

!4%

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

18090+

6arameters

Clinical studies ma* be re;uired to support claims for the efficac* and safet* of MR formulations. 1ioa)ailabilit* data should be obtained for all MR dose forms although the t*pe of studies re;uired and the pharmaco8inetic parameters which should be e)aluated ma* differ depending on the acti)e ingredient in)ol)ed. Bactors to be considered include whether or not the formulation represents the first mar8et entr* of the drug substance+ and the e(tent of accumulation of the medicine after repeated dosing. If the formulation is the first mar8et entr* of the drug substance+ the product-s pharmaco8inetic parameters should be determined. If the formulation is a second or subse;uent mar8et entr* then comparati)e bioa)ailabilit* studies using an appropriate reference product should be performed. Bor medicines where close control is critical the bioe;ui)alence of each strength of the formulation should be established. Bor other medicines+ if the formulations of different strengths are such that the proportion of e(cipients to the medicine are the same+ and ade;uate documentation of de)elopment pharmaceutics is pro)ided+ it is sufficient to establish the bioe;ui)alence of one strength. Bor formulations for which the drug substance or acti)e form# is unli8el* to accumulate in the bod* after multiple dosing AACT'.AAC 2.6#+ studies can be performed with single dose administration in the fasting state as well as following an appropriate meal at a specified time. The following pharmaco8inetic parameters should be calculated from plasma or blood or serum# concentrations of the medicine and.or maNor metabolite s#& AACT' AAC o)er the same inter)al following a single dose# AACt+ AAC+ Cma(+ and 8el. Bor formulations for which the drug substance or acti)e form# is li8el* to accumulate AACT'.AAC T2.6#+ studies should be performed with single dose administration in the fasting state as well as following an appropriate meal. In addition+ studies are re;uired at stead* state. The following pharmaco8inetic parameters should be calculated from single dose studies& AAC T'+ AACt+ AAC+ Cma(+ and 8el. The following parameters should be calculated from stead* state studies& AAC TC'' AAC measured o)er one dose inter)al at stead* state#+ C ma(+ Cpd the concentration immediatel* pre3 dose#+ Cmin+ and DB the degree of fluctuation in concentration as a proportion of the a)erage concentration o)er the dose inter)al#. ?here the ratio AACT'.AAC+ cannot be reliabl* determined+ it is to be assumed that accumulation occurs.

180903

'tudy design

It is necessar* to confirm the bioe;ui)alence of modified release products that are li8el* to accumulate and those that are unli8el* to accumulate+ both in the fasted and non3fasting state. If the effect of food on the reference product is not 8nown or it is 8nown that food affects its absorption#+ two separate %3 wa* cross3o)er studies+ one in the fasted state and the other in the fed state+ ma* be carried out. If it is 8nown with certaint* e.g. from published data# that the reference product is not affected b* food+ then a :3wa* cross3o)er stud* ma* be appropriate with !. the reference product in the fasting state %. the test product in the fasted state+ and :. the test product in the fed state.

!4:

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

180905

Re?uirements for modified release formulations unli2ely to accumulate

This section outlines the re;uirements for MR formulations which are used at a dose inter)al that is not li8el* to lead to accumulation in the bod* AACT'.AAC 2.6#. ?hen the MR product is the first mar8et entr* of that t*pe of dosage form+ the reference product should normall* be the inno)ator-s prompt3release formulation. The comparison should be between a single dose of the MR formulation and doses of the prompt3release formulation which it is intended to replace. The latter must be administered according to the established dosing regimen. ?hen the MR product is the second or subse;uent entr* on the mar8et+ comparison should be with the reference MR product for which bioe;ui)alence is claimed+ administered as single doses. The "2@ confidence inter)al calculated using log transformed data for the ratios Test&Reference# of the geometric mean AAC for both AACT' and AACt# and Cma( where the comparison is with an e(isting MR product# should generall* be within the range 62 to !%9@ both in the fasting state and following the administration of an appropriate meal at a specified time before ta8ing the medicine. The pharmaco8inetic parameters should support the claimed dose deli)er* attributes of the modified3 release dosage form.

180908

Re?uirements for modified release formulations li2ely to accumulate

This section outlines the re;uirements for MR formulations that are used at dose inter)als that are li8el* to lead to accumulation AACT'.AAC T 2.6#. ?hen a modified release product is the first mar8et entr* of the MR t*pe+ the reference formulation is normall* the inno)ator-s prompt3release formulation. 1oth a single dose and stead* state doses of the MR formulation should be compared with doses of the prompt3release formulation which it is intended to replace. The prompt3release product should be administered according to the con)entional dosing regimen. ?hen the MR product is the second or subse;uent MR entr*+ single dose and stead* state comparisons should normall* be made with the reference MR product for which bioe;ui)alence is claimed. The "2@ confidence inter)al for the ratio of geometric means Test&Reference medicine# of AAC for both AACT' and AACt# and Cma( where the comparison is with an e(isting MR product# determined using log3transformed data should generall* be within the range 62 to !%9@ when the products are compared after single dose administration in both the fasting state and the fed state. The "2@ confidence inter)al for the ratio of geometric means Test&Reference medicine# for AACTC''+ Cma(+ and Cmin determined using log3transformed data should generall* be within the range 62 to !%9@ when the formulations are compared at stead* state. The pharmaco8inetic parameters should support the claimed attributes of the modified3release dosage form. Pharmacod*namic data ma* reinforce or clarif* interpretation of differences in the plasma concentration data. ?here these studies do not show bioe;ui)alence+ comparati)e efficac* and safet* data ma* be re;uired for the new product.

!44

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

180:

Analytical Methods

Anal*tical methods and conditions of sampling should be full* described+ preferabl* in the form of a standard operating procedure. The chosen anal*tical methods should be ^state of the art^ for a gi)en anal*te and should be specific and ade;uatel* sensiti)e. Preference should be gi)en to chromatographic techni;ues such as high pressure li;uid chromatograph* <P0C# or gas chromatograph* GC#. Assa* )alidation see 'ection !9.5.!# should be conducted in the laborator* which generated the stud* data+ using the same anal*tical procedures. Hualit* control of assa*s+ while conducting the stud*+ is )ital. The in)estigators- criteria for accepting or reNecting assa* data should be stated clearl* in the protocol or stud* report. If an assa* procedure is to be used at different sites+ it should be )alidated at each site and cross3site comparabilit* of results and )ariabilit* should be established. Copies of all of the original chromatographic printouts e(cept for a few e(amples to demonstrate sensiti)it* and selecti)it*# need not be included in the stud* report. <owe)er+ the original printouts should be retained b* the in)estigators and be a)ailable on re;uest+ at least until Medsafe-s assessment and appro)al processes ha)e been completed.

180:01

(hromatogra)hic assay .alidation

Detailed )alidation data on the specificit*+ accurac*+ reproducibilit* and sensiti)it* of the anal*tical procedure and stabilit* of the anal*tes in plasma.serum or other applicable bod* fluids should be included in the stud* report. Specificity >)idence should be pro)ided that the assa* does not suffer from interference b* endogenous compounds+ degradation products+ other medicines li8el* to be present in stud* samples+ and metabolites of the medicine s# under stud*. Reference standards of metabolites will fre;uentl* not be a)ailable+ but in)estigators should address this problem as far as is practicable. Stability of measured medicine:metabolites Data should be accumulated which establish the stabilit* of the measured entities normall* parent medicine and.or acti)e metabolites# in the rele)ant biological en)ironment from time of sampling to assa*+ under the conditions and duration of storage that appl*. The absence of an* sorption b* the sampling containers and stoppers should also be established. &inimum 9uantifiable concentration (&;.) This is a contentious issue and man* approaches are encountered. Terms such as Xlimit of detectionX and Xminimum detectable concentrationX ma* be misleading in this conte(t since it is t*picall* possible to detect ;uantities of an anal*te substantiall* below those which can be assigned a meaningful ;uantitati)e )alue. The parameter ^three times baseline noise^ is often encountered in this conte(t+ but reflects what concentration can be detected rather than what can be ;uantified. A better approach is to define the MHC as the lowest concentration which has an inter3da* coefficient of )ariation for multiple inNections of %2@ as well as this can be measured#. It is not necessar* to define a MHC if the lowest concentration encountered during sampling has a coefficient of )ariation of less than %2@ during assa* )alidation. Shape of calibration cur!e 0inearit* is preferred. The shape of the calibration cur)e should be defined in mathematical terms on more than one occasion optimall* three#+ preferabl* o)er a concentration range from the MHC to a )alue greater than the C ma( e(pected in the stud*. Calibration standards in the !+%+9+!2+%2+92 3333333 pattern of concentration are preferable. The coefficient of determination r %# should normall* e(ceed 2."" r ] 2.""9#. Alternati)e approaches ma* be used pro)ided Nustification is supplied.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

,ssay precision and accuracy Precision the degree of reproducibilit* of indi)idual assa*s# is established b* replicate assa*s on standards+ preferabl* at se)eral concentrations. Accurac* is the degree to which the Otrue- parameter of the medicine is estimated b* the assa*. Precision and accurac* should normall* be documented at three concentrations low+ medium+ high# where Olow- is in the )icinit* of the lowest concentration to be measured+ Ohigh- is a )alue in the )icinit* of Cma( and Omedium- is a suitable intermediate )alue. Intra3assa* precision within da*s# in terms of coefficient of )ariation should be no more than !2@+ although no more than %2@ ma* be more realistic at )alues near the MHC. Inter3assa* precision between da*s# ma* be higher than !2@ but not more than %2@. Accurac* can be assessed in conNunction with precision and is a measure of the e(tent to which measured concentrations de)iate from true or nominal concentrations of anal*tical standards. In general+ an accurac* of `!2@ should be attained. *eco!ery Documentation of e(traction reco)er* at high+ medium and low concentrations is essential since methods with low reco)er* are+ in general+ more prone to inconsistenc*. If reco)er* is low+ alternati)e methods should be in)estigated. Reco)er* of an* internal standard used should also be assessed.

180:0+

Radioimmunoassays

'imilar principles appl* to chromatographic and bioassa*s such as radioimmunoassa*s and pharmacological procedures+ but the details ma* )ar*. In addition to the principles outlined for chromatographic methods in 'ection !9.5.!+ the following points relate to radioimmunoassa*s. ,ntibody The characteristics of the radioimmunoassa* depend on the antibod*+ which )aries from animal to animal. Therefore+ the following )alidation details should be repeated for each new batch of antibod*& specificit*+ calibration cur)e+ MHC+ precision+ and accurac*. It is preferable to use the same batch of antibod* for the whole stud*. Specificity (cross-reacti!ity) Data should be pro)ided that demonstrate which part of the antigen is binding to the antibod*+ as well as the degree of binding of closel* related substances such as metabolites and brea8down products at the antibod* titre emplo*ed. 'pecific antibodies should be emplo*ed. .alibration cur!e Bor radioimmunoassa*s+ calibration cur)es should be fitted to a computer model or transformed b* a logit anal*sis to gi)e a linear relationship between percent bound and concentration of anal*te. .ontrols Controls for radioimmunoassa* should include blan8s comprising pre3dose samples e.g. plasma# from each subNect in the stud*. These should demonstrate that the assa* does not indicate the presence of antigen when it is absent. A set of standards from 2 to "2@ displacement of label is necessar*.

180:03

Assay of study sam)les

The following guidelines describe an acceptable approach to assa*ing samples. Daily calibration standards Calibration standards and a sample blan8 e.g. plasma# are anal*sed with each batch of stud* samples on a dail* basis. Two possible approaches are& use three concentrations of standards in triplicate. These can con)enientl* be the same three concentrations low+ medium and high# used to estimate precision and accurac* in the pre3stud* )alidationF or

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

use at least fi)e concentrations of standards from the MHC to the highest concentration encountered in the stud*. Calibration standards should be blan8 samples e.g. plasma# spi8ed with 8nown concentrations of medicine+ and prepared freshl* each da* from pure reference substance. 'eeded controls should be spaced throughout the batch. Bailure to obtain reproducibilit* and linearit* for the dail* standards necessitates re3assa* of the batch. Seeded controls 'eeded controls sometimes called Kspi8esL# are a )aluable component of in3stud* ;ualit* assurance. Control samples at three or more concentrations are prepared in plasma in bul8 at the time of pre3stud* assa* )alidation+ or at the time of stud* sample collection+ and are ali;uoted into storage )essels. A control for each concentration is assa*ed on each occasion that stud* samples are assa*ed+ and the concentration determined b* reference to that da*Xs calibration standards. If the concentration )alues determined for the controls are not within `!9@ of the e(pected concentrations+ the batch should be considered for re3anal*sis. If not within `%2@ of the e(pected concentrations+ the batch should be re3 anal*sed unless there is )er* good reason not to do so. 'eeded controls+ therefore+ pro)ide a constant reference point between batches of assa*s as well as determining whether the medicine is stable under the storage conditions used. *e-analysis of samples In most studies some samples will re;uire re3anal*sis because of aberrant results due to processing errors+ e;uipment failure or poor chromatograph*. The reasons for re3anal*sis of such samples should be stated. ?hen the results of repeat assa* differ from the original b* more than !9@+ a third anal*sis should be done. ?hen the three anal*ses indicate that one is spurious+ then the a)erage of the other two should be used. *ange of reported !alues Concentration )alues less than the lowest calibration standard should be reported as such and should not normall* be used in data anal*sis. Concentration )alues greater than the highest concentration used in the linearit* studies should be highlighted and accompanied b* )alidation data. Concentration )alues marginall* up to %2@# abo)e dail* calibration standards ma* be reported if pre3stud* linearit* data e(tended be*ond such )alues Concentration )alues less than the MHC should not be used in data anal*sis.

180;

Re)orting !ata

The concentration of the entities measured in the plasma.serum.blood for each subNect+ sampling time and formulation should be tabulated. An* de)iations e.g. missed samples or late collection of samples# should be clearl* identified in these tables. The order in which the formulations were administered to each subNect should also be indicated. Two graphs should be drawn for each subNect+ and two for the mean )alues of all subNects. =ne should be linear and the other a semi3logarithmic plot of the concentrations from the reference and test formulations against sampling times. It is preferable that the semi3logarithmic plots should also displa* the regression lines which were emplo*ed to estimate the terminal elimination rate constants. Alternati)el*+ the number of points used ma* be indicated or tabulated elsewhere in the stud* report. ?here plasma concentration data ha)e been generated+ the minimum acceptable pharmaco8inetic data set for each subNect and each treatment is&

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

Ci< C%a5 Generall* this should be reported as the highest measured concentration+ rather than a )alue obtained from cur)e3fitting. The ade;uac* of such data is a function of the sampling inter)als in the )icinit* of Cma(. Cii< T%a5 Generall* this should be reported as the time at which C ma( was obser)ed+ using actual sampling times rather than nominal times or )alues obtained from cur)e3fitting. Ciii< 8Ct The area under the cur)e to the last sampling time AACt# should be calculated b* the trape/oidal rule the area contribution for each sampling inter)al is the mean of the concentrations at the beginning and end of the inter)al multiplied b* the length of the inter)al#. The actual sampling times+ rather than the nominal times+ should be used in the calculations. Ci&< 8C

Bor single dose studies+ the area under the cur)e to infinit* AAC# should be calculated using the e;uation& $-C . $-Ct / Ct0kel

where Ct is the plasma concentration at the last sampling time t and 8el is the terminal elimination rate constant where plasma concentrations fluctuate in the terminal region of the cur)e+ it is preferable to estimate Ct from the log.linear plot of plasma concentrations against time#. Tabulations of the proportion of AAC which is e(trapolated+ should be pro)ided. C&< 6el Cor tH< Tabulations of 8el or tJ# should be pro)ided. C&i< 3ther Para%eters =ther parameters+ such as total urinar* e(cretion+ ma* need to be calculated in some cases.

180<

6resentation of 'ummarised !ata

All bioa)ailabilit* parameters should be tabulated+ preferabl* as mean ` standard de)iation with the obser)ed range gi)en in parenthesis Ce.g. AAC E %9 ` 6 5342# ng.h.ml3!D. The units of measurement for the parameter should alwa*s be gi)en. It is important to specif* whether measured medicine concentrations refer to plasma+ serum or whole blood concentrations. ?here appropriate+ AAC and C ma( and statistical anal*ses should be normalised for medicine content mean assa*# of both dosage forms. Ratios and confidence inter)als should be normalised if the potencies of the batches of medicines compared differ b* more than :@ and.or the calculated confidence inter)als lie close to the 62@ or !%9@ limits and normalisation could affect the conclusion. It should be clearl* stated in the stud* report whether data ha)e or ha)e not been normalised.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

1801,

'tatistical Analysis

The following statistical methods should be used in the anal*sis of bioa)ailabilit* trial data. =ther methods of anal*sis ma* be acceptable+ but their use should be Nustified. 'tatistical comparisons between formulations should be based on data deri)ed from indi)iduals and not onl* on a)eraged data.

1801,01

Num*er of su*Jects

The minimum acceptable number of subNects is usuall* !%. <owe)er+ the number of subNects should pro)ide the stud* with a sufficient statistical power usuall* 62@# to detect the allowed difference usuall* %2@# between the test and reference medicines for AAC and C ma(. This number n# ma*+ in man* cases+ be estimated in ad)ance from published or pilot stud* data using the following formula& n !3a# s% 1 2s202 2t / t342

3 3 3

t+ ta

the re;uired significance le)el of the stud* and is e;ual to 2.29. the re;uired minimum power of the stud* and is normall* not less than 2.62 the residual# error mean s;uare from a cross3o)er AN=$A the allowed difference re;uired to detect as a proportion of the mean for the reference treatment. is generall* ta8en to be 2.% ( mean for reference# and should be in the same units as s. the one3tailed 'tudent t distribution )alues for and respecti)el*. The degrees of freedom for t are those of the AN=$A residual# error mean s;uare.

?here the data are log3transformed+ s% is the residual# error mean s;uare from the cross3o)er AN=$A of the logarithms of the AAC or Cma( )alues+ and is the logarithm of !.%2. 1ecause n is un8nown a -riori+ it will be necessar* initiall* to use )alues of the Normal distribution parameters / and /a in place of the 'tudent Ot- distribution parameters t and ta to deri)e an estimated )alue for n and subse;uentl* to perform a simple iteration using this initial estimate to determine n more precisel*.

It will be necessar* to obtain estimates of s% and the reference mean using mean and standard de)iation data from the literature and.or from the pilot stud*. <owe)er+ as the stud* )ariance ma* differ from the literature or pilot stud* )alues+ it would be prudent to err on the side of generosit* in numbers. If the calculated number of subNects appears to be higher than is ethicall* Nustifiable+ it ma* be necessar* to accept a statistical power which is less than desirable. It is usuall* not ethicall* Nustifiable to use more than about 42 subNects.

1801,0+

Analysis of .ariance -AN$VA/

Anal*sis of )ariance AN=$A# is a techni;ue for in)estigating how much of the total )ariabilit* in a set of obser)ations can be ascribed to different causes. The components of the )ariances are anal*sed further to tests the null h*pothesis <2 that all of the samples ha)e been drawn from the same population. The alternati)e h*pothesis <! is that one or more s*stematic differences e(ist. An AN=$A ta8ing account of subNects+ se;uence+ period phase# and treatment formulation# effects should be performed for C ma(+ AAC+ T ma( and other parameters as appropriate to determine if there are an* statisticall* significant differences. A more comple( AN=$A ma* be appropriate in some

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

circumstances+ for e(ample if treatments are replicated or if a stud* has been conducted as two independent phases. The assumptions underl*ing such an AN=$A are& Randomisation of samples. The subNects chosen for the stud* should be randoml* assigned to the se;uences of the stud*.# <omogeneit* of )ariances. The )ariances associated with the two treatments+ as well as between the se;uence groups+ should be e;ual or at least comparable.# Additi)it* linearit*# of the statistical model. There should be no interactions between the subNect+ se;uence+ period and treatment effects for a standard % ( % cross3o)er stud*.# Independenc* and normalit* of residuals. The residuals of the model should be independentl* and normall* distributed.# The assumptions of normalit* of residuals and homogeneit* of )ariance in the model are 8nown to be relati)el* robust. That is+ small or moderate departure from each or both of these assumptions will not ha)e a significant effect on the final result. If there is significant e)idence of departures from the assumptions then a parametric AN=$A should not be performed on the raw data. If the assumptions abo)e are not met+ the data should be transformed prior to the AN=$A. A non3 parametric anal*sis should be used e.g. T ma( see below#. Man* biological data correspond more closel* to a log3normal distribution than to a normal distribution. In particular+ the parameters AAC and C ma( tend to be s8ewed and their )ariances to increase with their means. 0og transformation is li8el* to remed* these defects and ma8e the positi)el* s8ewed distributions more s*mmetrical. Conse;uentl*+ AAC and C ma( data should be log transformed prior to statistical anal*sis. The primar* comparison of interest in a bioe;ui)alence stud* is the ratio+ rather than the difference+ between a)erage parameter data from the test and the reference formulations. Asing log3transformation in the anal*sis allows inferences about the difference between the two means on the log scale. Re3 transformation then allows inferences about the ratio of the a)erages on the original scale. 0og transformation thus achie)es a comparison based on a ratio rather than on a difference. Non3parametric anal*ses e.g. tests based on ran8s and computation of "2@ confidence inter)als for differences between test and reference medicine# should be used for T ma( data as the obser)ed )alues are discrete e)en though the underl*ing distribution is continuous.

1801,03

(onfidence inter.als

It is recommended that confidence inter)al methods be used instead of h*pothesis tests in the estimation of relati)e bioa)ailabilit*. The "2@ confidence inter)al for the ratio between the test and reference geometric means for AAC and C ma( should be determined using log3transformed data. Confidence inter)als wholl* within the range of 2.62 to !.%9 will generall* be accepted as an e;ui)alence criterion for AAC and Cma(. The non3parametric "2@ confidence inter)al for the difference in T ma( between the formulations should lie within a clinicall* acceptable range.

1801,05

6ower of AN$VA

Calculation of power is necessar* whene)er two formulations ha)e been directl* compared in terms of a null h*pothesis of /ero difference in conNunction with an AN=$A.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

The power of a %3wa* AN=$A accounting for treatments and subNects# to detect a difference between two means amounting to a gi)en fraction of the mean of the reference formulation can be calculated for each bioa)ailabilit* parameter according to the following e;uation& t3 ?here& !3a n s% 3 3 3 3 3 3 power the degrees of freedom of the AN=$A residual# error mean s;uare fraction of mean of the reference formulation number of subNects residual# error mean s;uare from the AN=$A the re;uired significance le)el of the test and Ot- )alues are one3tailed . 2n02s24 5 t

?here the data are log3transformed+ s% is the residual# error mean s;uare from the cross3o)er AN=$A of the logarithms of the AAC or Cma( )alues+ and is the logarithm of !.%2. Ade;uate sensiti)it* of the statistical test is usuall* defined as a power of at least 2.6 62@# with E 2.29. 'trictl*+ the abo)e e;uation should not be applied to a :3wa* AN=$A. In practice+ howe)er+ since an* se;uence effect is usuall* small+ it gi)es a reasonable appro(imation of the power.

18011

!ata Re?uirements

The bioe;ui)alence stud* report should include as a minimum# the following information& Table of contents Title of stud* and an* rele)ant reference Names and affiliations of the responsible in)estigators 'ignatures of the principal and other responsible in)estigators authenticating their respecti)e sections of the report 'ite of the stud* The period of dates o)er which the stud* was conducted Names and batch numbers of the products compared The formulation of the test product s# or a signed declaration that this was identical to that intended for mar8eting Results of assa*s and other pharmaceutical tests e.g. ph*sical description+ dimensions+ mean weight+ weight uniformit*+ comparati)e dissolution# carried out on the batches of products compared The full protocol for the stud* including a cop* of the informed consent form and the criteria for inclusion+ e(clusion or remo)al of subNects Documentar* e)idence that the stud* protocol was appro)ed b* an appropriate independent ethics committee or institutional re)iew board and was carried out in accordance with good clinical and laborator* practice Age+ height+ weight+ ethnicit* and smo8ing habit data for the subNects Results of clinical and laborator* screening tests Details of and a Nustification for an* de)iations from the protocol Details of an* ad)erse reactions obser)ed Details of an* withdrawals from the stud* Details of anal*tical methods used+ full )alidation data+ ;ualit* control data and criteria for accepting or reNecting assa* results Representati)e chromatograms

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

Actual sampling times All indi)idual and a)eraged assa* results presented in a clear wa* both tabular and graphical as appropriate# Details of how pharmaco8inetic parameters were determined Indi)idual and summarised a)erage pharmaco8inetic parameters Details and results of statistical anal*ses Pustification for an* departures from con)entional statistical methodolog*. 'ummar* and Conclusions Copies of an* literature referred to in the report and not readil* a)ailable

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

'ection 19:

E?ui.alence #esting of &nhaled Medicines

Section summary "his section descri+es how to design and conduct a study to com-are the clinical efficacy of different formulations or +rands of inhaler -roducts#

1901

&ntroduction

All applications to mar8et multi3source metered dose inhalers and other inhaler de)ices must be supported b* data establishing ph*sical and clinical e;ui)alence with the reference product. 'imilarl*+ applications to mar8et inhalers where a chlorofluorocarbon CBC# propellant has been replaced with a non3CBC propellant must be supported b* data establishing e;ui)alence with the pre)iousl* appro)ed CBC3containing product. The following guideline for establishing e;ui)alence of inhalers draws upon the maNor pharmacopoeia and the following o)erseas guidelines& Guidelines on the -re-aration of :--lications to Register Metered 7ose :erosols A1ressurised and Non4-ressurisedB+ Appendi( %4 in ^Australian Guidelines for the Registration of Drugs^ Therapeutic Goods Administration& Canberra+ Pul* !""4. Re-lacement of chlorofluorocar+ons A%F%sB in metered dose inhalation -roducts, CPMP Note for Guidance III.9:56.":+ December !"":. 7raft guidelines on in !i!o criteria to esta+lish e ui!alence of safety and efficacy of a multi4source or second entry drug deli!ered +y metered dose inhaler for drugs intended for deli!ery to the lower res-iratory tract. <ealth Protection 1ranch+ <ealth and ?elfare Canada& =ttawa+ !""%. The 1ritish+ >uropean and Anited 'tates Pharmacopoeia 1P+ Ph >ur and A'P# include details of the general re;uirements for ;ualit* control and the )arious ph*sical tests and test e;uipment appropriate for metered dose inhalers and other inhaler de)ices. The specifications for the ingredients+ containers and metering de)ices+ the in process controls during manufacture+ and the release and shelf3life specifications for the finished product should ade;uatel* control the following& defecti)e containers and metering de)ices+ pressure testing+ lea8age rates+ moisture content+ acti)e substance deli)ered per dose mean and dose uniformit*#+ number of doses deli)ered+ and deposition of dose. Details of the de)elopment of the product and Nustification for each formulation should be pro)ided in the application dossier. Information should be supplied on the following& e(cipients chosen+ component.propellant ratios+ e(tractables from the elastomeric components of the de)ice+ microbial testing+ metering )al)e performance and control+ consistenc* of deli)er* of dose o)er time+ o)er the life of the canister+ and with or without priming of the )al)e+ ;ualit* of acti)e ingredient including cr*stal form+ if rele)ant#+ and particle si/e distribution b* mass of the acti)e ingredient e(cept in cases where the acti)e ingredient is in solution at an* stage of the finished product manufacturing process#.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

190+
190+01

6hysical e?ui.alence
Measuring )article si@e distri*ution

Particle si/e distribution of the inhaled aerosol or powder can significantl* affect deposition within the respirator* tract. It is important that the mass distribution rather than the number distribution of the aerosol particles be determined+ and that the particles measured actuall* contain the medicine. 1ecause of the non3uniformit* of material distribution in pol*3disperse droplets and particles which are ph*sicall* and chemicall* heterogeneous+ it is critical that the si/ing method be able to distinguish the acti)e substance from other components of the aerosol. The probabilit* that an* gi)en aerosol droplet contains the acti)e substance is dependent on the drug concentration and both droplet and drug particle si/e. 0ight scattering or optical methods are unsuitable for pressurised aerosols as the* are unable to distinguish between droplets containing drug and those containing onl* e(cipients+ and do not gi)e an* information about the aerod*namic diameter of the particles. ?ith the e(ception of microscop* the* are+ howe)er+ suitable for routine ;ualit* assurance of aerosols generated from solutions+ or dr* powder inhalers which contain no e(cipients+ particularl* where the diameter of particles is % micrometres. The most direct method for determining particle si/e distribution is to fractionate the material b* impaction using a multistage li;uid impinger or a multistage cascade impactor+ each with sufficient stages to enable the distribution to be defined ade;uatel*. The amount of drug substance in each fraction is then determined. Instruments are commerciall* a)ailable which ha)e been factor* calibrated using mono3disperse aerosols at )arious flow rates. Careful design of the input port of the inhaler de)ice is re;uired to ta8e into account initial deposition of the aerosol in the mouth resulting from incomplete e)aporation of the propellant+ and to reduce the chances of o)erloading the first stage of a cascade impactor. The use of a large e(pansion chamber for the input port is not recommended as it would effecti)el* act as a spacer. Input ports similar to those in Apparatus A or 1 of the 1P are suitable. In determining the particle si/e distribution of a product b* cascade impaction+ the number of actuations emplo*ed per replicate should be 8ept to a minimum to a)oid the mas8ing of )ariations+ and should be consistent with the limit of sensiti)it* of the best a)ailable assa* method. If a manufacturer does not carr* out the si/ing under appropriate conditions or cannot pro)ide a rational ;uantitati)e estimate of h*groscopic growth b* an indirect method+ then a Nustification should be pro)ided as to wh* such data are not necessar*. If the mass of the particles is log3normall* distributed+ the mass median aerod*namic diameter and the geometric standard de)iation of the particles gi)e a good characterisation of the aerosol. The distribution pattern of two aerosols can then be compared statisticall*. The "2@ confidence inter)als for the ratio of the mass median aerod*namic diameters ma* also be a useful parameter for comparison of two products. In cases where the particle si/e distribution of aerosols de)iates significantl* from log3normal+ comparison of the respirable and non3respirable fractions ma* be more useful. ?hile the twin3impinger method for determining the particle si/e of pressurised aerosols such as that adopted b* the 1P# is based on measurement of the drug mass aerod*namic diameter+ it is limited in that onl* % fractions can be collected particles abo)e and below appro(imatel* 7.9 micrometres in the case of the 1P#. Therefore+ a complete aerod*namic mass distribution cannot be defined.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

It follows that the twin3impinger method is generall* not useful for product de)elopment nor for comparison of multi3source and inno)ator metered dose aerosols+ although it ma* be suitable for routine ;ualit* control of products. The twin impinger ma* also be acceptable for product de)elopment where a manufacturer has established an in !itro 5 in !i!o correlation for the product in ;uestion. Comparison of the particle si/e distributions of different products should be carried out under conditions which are clinicall* rele)ant. Bor e(ample& slow flow rates of %93:9 0.min3! are li8el* to reflect the Oworst possible- case of the effect of inspiration on de3aggregation of dr* powders b* patients unable to breathe at a faster rate dr* powder inhalers generall* produce smaller particle si/es at higher flow rates+ and with propellant3dri)en generators+ slow flow rates ma* produce unrealisticall* small particle si/es b* allowing e(cessi)e time for e)aporation of the propellants. A rationale should be pro)ided for whate)er the flow rate and other test conditions are chosen+ preferabl* reflecting in !i!o data and.or clinical use.

190+0+

6article si@e

Bor corticosteroids and other medicines where side effects ma* follow orophar*ngeal deposition+ it is recommended that specifications be established for the& ma(imum amount of drug lea)ing the aerosol generator and li8el* to deposit in the orophar*n( aerod*namic diameter greater than appro(imatel* 4.5 micrometres#F and amount li8el* to deposit predominantl* at the desired sites i.e. the amount of drug contained in aerod*namic si/e fractions below appro(imatel* 4.5 micrometres#. The actual cut3off diameters ma* )ar* from one therapeutic class of medicine to another. This )ariabilit* should be based on clinical e)idence of optimum site of deposition. Bor e(ample+ for new beta3% agonists the optimum mass particle si/e distribution is in the order of ]42@ below :34 micrometres aerod*namic diameter so as to ensure acceptable airwa*s penetration.

1903

(linical E?ui.alence

The minimum re;uirement for establishing clinical e;ui)alence is a comparison of clinical efficac* with the reference product+ in a properl* designed and conducted stud* of acceptable statistical power. The stud* should incorporate appropriate monitoring of ad)erse effects. Pharmacod*namic measurements should be incorporated in the protocol. Applicants must pro)ide certification that the stud* was carried out with >thics Committee or Institutional Re)iew 1oard appro)al+ using appropriate codes of Good Clinical Research Practice. 1ronchoconstriction ma* occur in sensiti)e indi)iduals during clinical studies comparing products which do not contain a bronchodilator. Therefore+ all clinical studies in)ol)ing products containing non3bronchodilator medicines should include measures to detect bronchoconstricti)e responses. 'upporting clinical and ph*sical particle si/e distribution# data are re;uired for spacer de)ices recommended for use with inhaled products. These data should be generated for each product recommended for use with each spacer de)ice.

190301

'tatistical analysis

?hen conducting clinical trials to compare two similar metered dose inhalers such as two bronchodilators# the confidence inter)al approach would be an appropriate form of statistical anal*sis. The procedure is outlined abo)e in 'ection !9.!2.

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In general+ two products ma* be considered clinicall* e;ui)alent if their relati)e effect does not differ b* more than %2@+ i.e. if the confidence inter)al for the effect ratio of multi3source to reference product calculated using log3transformed data# falls within the range 623!%9@. <owe)er+ a confidence inter)al width of 623!%9@ ma* not alwa*s be appropriate for clinical studies for non3steroidal proph*lactic products and glucocorticoids+ due to the inherentl* greater )ariabilit* in such studies. The applicant should Nustif* an* confidence inter)al falling be*ond 623!%9@.

19030+

='ym)athomimetic medicines

The minimum re;uirement to establish the bioe;ui)alence of a multi3source 3s*mpathomimetic product against the reference product is a comparison of&

i#

the bronchodilator effect+ using the forced e(pir* )olume in one second B>$!# and.or measurements of the area under the cur)e AAC# for B>$! o)er time in mild to moderate asthmaticsF and ii# the broncho3protecti)e effect+ using controlled challenge tests such as a histamine pro)ocation test. 'ubNects participating in bronchodilation and broncho3protecti)e effect studies should ha)e re)ersible airflow obstruction. The* should be stable asthmatics who ha)e shown a bronchodilator response of at least %2@+ and ha)e been shown to be stable for at least 4 wee8s prior to the stud*+ that is+ their le)els of s*mptoms and medication should be constant and the* should be free from )iral infections. The stabilit* of B>$! between stud* da*s should be assured i.e. !9@ or below is preferable# and there should be guidelines on the continuation or cessation of other medication. 'low release theoph*lline should be withheld for at least %4 hours prior to the stud*+ and other inhaled bronchodilators for an ade;uate washout period. =n the stud* da*+ subNects should be stable for half an hour before the stud* commences and medicine administration should be standardised. /ronchodilation A double blind placebo3controlled cross3o)er stud* should be conducted to compare !+ %+ and 4 puffs of reference product )ersus % puffs of the multi3source medicine )ersus % puffs of placebo in stable asthmatics to measure the ma(imum increase in B>$ ! time course and duration of bronchodilation. Two puffs of the multi3source product should ha)e significantl* greater effect than ! puff of reference product+ and less effect than 4 puffs of reference product p T 2.29#. Two puffs of the reference and % puffs of the multi3source product should not be significantl* different p] 2.29#. /roncho8protective effects A double blind placebo3controlled methacholine challenge cross3o)er stud* nE!7# should be conducted to compare !+ %+ and 4 puffs of reference product )ersus % puffs of multi3source product )ersus % puffs of placebo in stable asthmatics. The dose of methacholine re;uired to induce a %2@ fall in B>$ ! of a patient pre3treated with a3agonist at the time of e(pected ma(imum effect should be measured and the time course and duration of the effect should be e(amined. The higher the challenge dose of methacholine re;uired+ the higher the protecti)e effect of the beta3agonist. The multi3source product must not produce a significantl* worse cardio)ascular response or a significantl* greater incidence of ad)erse e)ents than the reference product. A spacer de)ice could be used for the stud* if it is recommended that the de)ice routinel* be used with the product. Bor multi3source 3s*mpathomimetics+ it is accepted that two products are considered clinicall* e;ui)alent if their relati)e effect does not differ b* greater than %2@+ i.e. if the "2@ confidence inter)al calculated using log3transformed data# lies within the range 623!%9@ of the )alue for reference

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product. This range would also ta8e into account the e(pected consistenc* of o)erall deli)er* of medicine from the product. 'tud* numbers should be based on power calculations to detect a difference if one reall* e(ists e.g. "2@ power to detect a %2@ difference at the 2.29 le)el#. AAC for B>$! o)er time should usuall* be measured for a sufficient duration to define full* each response cur)e. >(trapolation to infinite time is not necessar*. Pro)ided the baseline is tightl* controlled+ it would be sufficient to base the comparisons on absolute )alues. If no difference in efficac* is shown b* the stud*+ and the propellants and dispersing agents in the multi3source product are not new to aerosol formulations+ then no further clinical studies should be re;uired.

190303

Anticholinergic medicines

The principles appl*ing to establishing clinical e;ui)alence of 3s*mpathomimetic medicines outlined abo)e in 'ection !7.:.% also appl* to applications for consent to distribute multi3source inhalers containing anticholinergic agents.

190305

Non=steroidal )ro)hylactic medicines

Applications for consent to distribute multi3source medicines used for the proph*lactic treatment of asthma+ b* inhibition of the release from effector cells of mediators of the allergic reaction+ should be supported b* acute clinical studies and sometimes+ long term clinical studies# comparing efficac* against the reference product. A comparison of their abilit* to protect against a challenge such as cold air+ e(ercise+ or sulphur dio(ide# ma* suffice. Pro)iding this stud* shows e;ui)alent performance+ and the aerod*namic beha)iour of the products is comparable+ no further studies are re;uired. <owe)er+ if a difference in effect is shown b* the acute stud*+ long term comparison of clinical efficac* such as impro)ement of spirometr* or a reduction in the need for medication# or a stud* defining the in4!i!o deposition profile of the multi3source inhaler in relation to the reference will be re;uired. As determination of pharmacod*namic effects for non3steroidal proph*lactic medicines are inherentl* more )ariable than those for bronchodilators+ appropriate allowance should be made in terms of discriminator* power and acceptable difference.

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190308

Glucocorticoids

Bor inhaled glucocorticoids+ two methods can be used to establish clinical e;ui)alence. These are described in guidance notes published b* the >uropean Commission-s Committee for Proprietar* Medicinal Products CPMP# and <ealth Canada. The CPMP Note for Guidance& Re-lacement of chlorofluorocar+ons A%F%sB in metered dose inhalation -roducts gi)es the following ad)ice and procedure for establishing e;ui)alence of glucocorticosteroid inhalers& KThe demonstration of clinical bioe;ui)alence of inhaled glucocorticosteroids is difficult and at this stage in our 8nowledge the onl* definiti)e efficac* studies are the parallel group Khead3to3 headL direct clinical comparisons+ preferabl* in steroid3nai)e patients+ with demonstration of clinical efficac* based on assessments made b* the patient at home+ recorded on diar* cards+ and made at regular+ sa* % wee8l*+ inter)als in the clinic. Assessments would include pulmonar* function measurements+ s*mptoms scores+ inhaled bronchodilator re;uirements and rate of e(acerbations+ defining beforehand an ade;uate primar* outcome3)ariable. 'tudies should address a particular disease se)erit*.dose regimen. The duration of treatment would need to be a minimum period of 4 wee8sF longer treatment periods ma* be ad)antageous. 'ince impro)ement in patients who are stabilised on corticosteroids is unli8el*+ the use of such patients is discouraged. <owe)er+ if patients on corticosteroids must be entered into a trial+ the pre3entr* criteria+ the e(pected impro)ements and the si/e and duration of the trial should be Nustified. 'ingle dose allergen challenge studies are artificial compared with natural e(posure. There is a bod* of e)idence which would support the use of the late response as a clinical model for the e)aluation of potential new therapeutic agents+ for earl* dose ranging in Phase II studies and the in)estigation of basic mechanisms of allergic asthma. <owe)er+ there is )er* little information on the reproducibilit* or dose3dependenc* of the late response and therefore its use in the demonstration of clinical bioe;ui)alence is e(tremel* limited and would not be appropriate. Appropriate safet* monitoring should be carried out+ including some measure of s*stemic effect+ e.g. assessment of h*pothalamic adrenocortical function and assessment of parado(ical bronchospasm.L The Canadian 7raft guidelines on in !i!o criteria to esta+lish e ui!alence of safety and efficacy of a multi4source or second entry drug deli!ered +y metered dose inhaler for drugs intended for deli!ery to the lower res-iratory tract, published b* the <ealth Product and Bood 1ranch of <ealth Canada describe a different approach where dose bac83titration is used to determine if the minimum effecti)e dose is the same for the reference and test product. The products are compared in a double blind parallel3group comparison in asthmatic patients alread* controlled on inhaled steroid e.g. a minimum of 622_g beclomethasone per da*#. The dail* dose of steroid is reduced in a stepwise manner e.g. b* %22_g.dose each wee8# until patients ha)e an e(acerbation of their asthma. The e(acerbation is treated b* resuming twice the pre)ious minimum dose of steroid. There must be no statisticall* significant difference in the dose of inhaled steroids between the reference and test product at the time of e(acerbation in the two groups. 'tud* numbers should be based on power calculations to detect a difference if one alread* e(ists e.g. "2@ power to detect a %2@ difference at the E 2.29 significance le)el#. Ad)erse effects such as d*sphonia+ thrush+ adrenal suppression should be monitored in these clinical studies.

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1905

6owders for &nhalers

?here a new medicine is essentiall* the same as a product alread* on the mar8et+ an abridged application should be submitted. ?here the two products are not essentiall* the same+ a New Medicine Application including clinical safet* and efficac* studies is re;uired. The principles appl*ing to determination of e;ui)alence for pressurised inhalers, in terms of clinical re;uirements+ are applicable to powders for inhalation. As the deli)er* de)ice can significantl* alter the deposition profile of an inhaled powder+ changes in the de)ice can result in the modified s*stem being regarded as a new product. Comparati)e efficac* data are then re;uired. MaNor changes in the formulation of the inhaled powder itself must also be accompanied b* comparati)e efficac* data+ as the deposition profile ma* again be affected see 'ection !7.: for details#. Bor a minor change in the powder component of an alread* appro)ed product+ the medicine mass aerod*namic properties of the two formulations should be defined. If the two formulations displa* similar performances in !itro+ no further studies will normall* be re;uired. <owe)er+ if a difference is obser)ed+ clinical data to confirm e;ui)alence or a Nustification as to wh* such data are not re;uired+ should be pro)ided.

1908

Nasal &nhalation 6roducts

Nasal inhalations+ administered for a local effect+ should ha)e a particle si/e distribution appropriate for nasal application+ i.e. particles are greater than %2 micron aerod*namic diameter or the deposition data show that ]"2@ of particles are deposited in the nose. Nasal inhalation intended to be absorbed and produce a s*stemic effect should be supported b* in !i!o bioa)ailabilit* data as outlined in 'ection !9 1ioe;ui)alence Testing of =ral Medicines#.

1909

(hanges to (urrently Mar2eted 6roducts

'ponsors ma* propose changes to inhaled products with consent to distribute in New ,ealand. The change ma* be ma@or such as )al)e si/e or design of the inhaler# or minor such as a change in the content of propellant which has minimal effect on the partial pressure of the mi(ture#. Pro)iding the change is relati)el* minor+ ph*sicochemical methods such as measurement of drug mass aerod*namic particle si/e distribution of the changed and current products will normall* be sufficient to establish e;ui)alence of performance. <owe)er+ if a difference in ph*sical performance is found+ or if the proposed change is li8el* to cause a difference in particle si/e distribution or clinical effect+ either a clinical stud* or a Nustification as to wh* this is unnecessar* should be pro)ided.

190901

Ru**er or )lastic com)onents

An* notification to a product which in)ol)es+ or is li8el* to affect+ rubber or plastic components should include data establishing whether or not leaching occurs. If leaching occurs+ the identit* and ;uantities of the leached substances should be established and comment pro)ided on their to(icological and clinical implications.

19090+

Re)lacement of chlorofluorocar*ons

As the production and use of chlorofluorocarbons CBCs# is being phased out internationall*+ man* companies are replacing these propellants with non3CBCs. The >uropean Commission has produced the guideline Re-lacement of %hlorofluorocar+ons A%F%sB in Metered 7ose 9nhalation 1roducts

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CPMP Guideline III.9:56.":#. Applicants who wish to replace e(isting chlorofluorocarbons with alternati)e propellants should follow this guideline.

190903

(hanges to )owders for inhalation

As the deli)er* de)ice can ha)e a significant influence on the deposition profile of an inhaled powder+ an* modification to its design or method of operation usuall* means the modified product is a new product and thus re;uires full clinical as well as ph*sicochemical data. 'imilarl*+ a substantial change in the formulation of the inhaled powder+ such as addition of an agent to modif* its flow or h*groscopic properties or the remo)al or substitution of carrier+ will necessitate the same data because the deposition profile could change mar8edl*. Ph*sical measurements+ such as drug mass aerod*namic particle si/e distribution of the deli)ered aerosol+ are usuall* sufficient to support minor changes in the content of an e(cipient in an alread* appro)ed powder for inhalation or minor changes to the deli)er* de)ice. These data should be generated at se)eral flow rates. <owe)er+ if significant ph*sical differences are obser)ed+ either clinical data or a Nustification as to wh* such data are unnecessar* should be submitted. An* comparati)e efficac* stud* performed to support a change to a powder for inhalation should encompass the principles for establishing clinical e;ui)alence of inhaled products as outlined abo)e.

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'ection 1::

(lassification and Reclassification of Medicines

Section summary "his section e>-lains the -rocess for classification of medicines Legislation to read in conjunction with this section Medicines :ct 1&2, *ection &C Medicines %lassification %ommittee First *chedule to the Medicines Regulations 1&2. I :mendments AMedicines %lassificationB

1:01

Medicines (lassification (ommittee

The Medicines Classification Committee MCC# is a Ministerial ad)isor* committee whose terms of reference are to ma8e recommendations to the Minister of <ealth regarding the classification of medicines as prescription medicines+ restricted medicines or pharmac*3onl* medicines. As well+ the Committee will consider and report to the Minister on an* matter concerning the classification of medicines and access to medicines b* health professionals and the public. The MCC meets twice a *ear usuall* in April and =ctober# to discuss classification issues and to consider changes in the classification of medicines. 'ecretarial support is pro)ided b* Medsafe. The Committee comprises two nominees from each of the New ,ealand Medical Association and the Pharmaceutical 'ociet* of New ,ealand and two members of the Ministr* of <ealth+ one of whom is to be appointed as chairperson. Nominees are appointed for a three3*ear term and ma* be re3appointed for one further term of office. Ministr* members retain their appointments ^during the pleasure of the Minister^.

1:0+

(lassification categories

The Medicines Act defines three classification categories for medicines& Prescription &edicine Prescription medicines ma* be supplied onl* on the prescription of a medical or dental practitioner+ midwife or )eterinar* surgeon. The* ma* also be used b* a registered member of another specified health profession when permitted in the Birst 'chedule to the Medicines Regulations or amendments. *estricted &edicine also referred to as Pharmacist 5nly &edicine# Restricted medicines ma* be sold without a prescription+ but the sale must be made b* a registered pharmacist+ in a pharmac*+ and details of the sale must be recorded. Pharmacy-5nly &edicine also referred to as Pharmacy &edicine# Pharmac*3onl* medicines ma* onl* be sold in a communit* or hospital pharmac*+ or a shop in an isolated area that is licensed to sell that particular medicine. The sale ma* be made b* an* salesperson. Medicines in each of these classification categories are listed in the Birst 'chedule to the Medicines Regulations !"64 and amendments. Medicines not listed in the classification schedules are deemed to

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be unclassified+ and are referred to as General Sale &edicines. These medicines ma* be sold from an* outlet.

1:03

First 'chedule to the Medicines Regulations 1<;5

Medicines are generall* classified according to their acti)e ingredients. The international non3 proprietar* name INN# is the name of choice. If the medicine has more than one acti)e ingredient+ the acti)e with the most restricti)e classification determines the classification of the product. The Birst 'chedule to the Medicines Regulations is a list of acti)e ingredients grouped under their respecti)e classifications. There are se)eral Ocatch3all- classification statements in the 'chedules. Bor e(ample+ inNectables are pharmac*3onl* medicines unless the acti)e ingredient of the inNection has a more restricti)e classification in its own right. This means that an inNection can ne)er be a general sales medicine+ e)en when it onl* contains sodium chloride and water. Classification changes occur appro(imatel* e)er* si( months. Apdates ma* occur either through an amendment to the Medicines Regulations or through publication of a notice in the New Zealand Ga)ette# Amendments are usuall* published in Pune each *ear. ?hen chec8ing a classification+ refer to the latest amendment to the Regulations and an* subse;uent update published in the Ga)ette. Alternati)el*+ Medsafe-s web site includes an alphabetical list of medicine classifications.

1:05

(lassification of (ontrolled !rugs

Narcotics and certain ps*chotropic agents are regulated under the Misuse of Drugs Act !"59 as controlled drugs. The Act defines three classes of controlled drugs. These are Class A+ Class 1 further subdi)ided into Parts I+ II I III# and Class C further subdi)ided into Parts I to $II#. The controlled drugs in each class are listed in the 'chedules to the Misuse of Drugs Act. The Misuse of Drugs Act and Regulations contain the re;uirements for the manufacture+ sale+ suppl*+ prescribing and labelling of controlled drugs. Controlled drugs that are also medicines are re;uired to meet the re;uirements of both the Misuse of Drugs legislation and the Medicines legislation. ?here there is an* inconsistenc* between the two sets of legislation the Misuse of Drugs legislation ta8es precedence o)er the Medicines legislation. An* controlled drug named in Part $I of the Third 'chedule to the Misuse of Drugs Act and fulfilling the specified re;uirements is b* definition a pharmac*3onl* medicine and can be labelled as such in accordance with the Medicines legislation. All other controlled drugs must be labelled in accordance with the Misuse of Drugs Regulations.

1:08

(lassification of Medicines

The MCC recommends the classification of acti)e ingredients where these ha)e not pre)iousl* been scheduled. Most new acti)e substances are initiall* classified as prescription medicines. The MCC also considers applications for the reclassification of medicines.

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1:09

(lassification (riteria

To ;ualif* for a shift from prescription to o)er3the3counter =TC# status+ a prescription medicine should& ha)e been mar8eted for three *ears or more ha)e had wide use during those three *ears ha)e a low ad)erse reaction profile with serious reactions occurring onl* rarel*+ and be suitable for =TC sale.

Note: The three3*ear period of use need not ha)e been in New ,ealand. <owe)er+ it must ha)e been in a countr* with a well3de)eloped pharmaco)igilance s*stem. The MCC uses the following definition adopted in !""2 b* the Commission of the >uropean Communities for suitabilit* for =TC sale& Medical -roducts which may +e a!aila+le without -rescri-tion shall show a su+stantial safety in use in the treatment of minor ailments or sym-toms, usually ca-a+le of ra-id and s-ontaneous relief, which are easily identifia+le +y users and do not @ustify a medical consultation# The Committee considers the following factors when re)iewing a medicine for reclassification for =TC sale. The list is not ran8ed in an* order of importance. The criteria ma* )ar* in importance according to the medicine being considered for reclassification. In some cases one factor alone ma* be sufficient to outweigh all others in determining whether or not a medicine should be reclassified. !onsumer convenience Accessibilit* of the medicine and suitabilit* for self3treatment. Accessibilit* includes time and location factors. Conditions suitable for self3treatment are usuall* minor and self3limiting. Potency The abilit* of a medicine to produce a wanted pharmacological effect. !urrent availa,ility The a)ailabilit* of products with a similar therapeutic purpose. ;herapeutic inde) The margin between therapeutic and to(ic effects. ;o)icity The potential of a substance to produce ad)erse preclinical and clinical effects. Ad)erse clinical effects will be assessed b* fre;uenc* and se)erit*. #,use potential The use of a medicine for gratification3producing effects not re;uired for therap*. $nappropriate use Bactors rele)ant to the minor ailment or s*mptom for which the medicine is indicated+ including the suitabilit* of the condition for self3monitoring and the li8elihood of misdiagnosis.

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Precautions Bactors rele)ant to the medicine under consideration such as contraindications+ side3effects and interactions with other medicines. !ommunal harm The possibilit* of communit* harm resulting from wider use of the medicine in ;uestion+ e.g. the de)elopment of antibiotic resistance in bacteria.

1:0:

(lassification 6rocess

It ta8es appro(imatel* si( months from the date a submission is lodged until the classification change is notified in the NZ Ga)ette# A ma(imum of 7 further months is allowed in the legislation for companies to amend labelling to reflect classification changes. There are nine phases in the classification process+ as outlined below. Phase 1: +u,mission ?hile applications usuall* come from sponsor companies+ an*bod* ma* ma8e a submission to MCC for the reclassification of a medicine. Closing dates for submissions to MCC are the end of Panuar* and the end of Pul* each *ear. 'ubmissions are placed on the agenda for the ne(t meeting. 1ecause of the need for consultation+ late items cannot usuall* be accepted. 'ubmissions are re)iewed b* Medsafe e)aluators+ and a report is forwarded to Committee members along with the original submission. Phase 2: !onsultation Immediatel* following the closing date for submissions+ forthcoming agenda items are posted on Medsafe-s web site. This pro)ides an opportunit* to send written comment on reclassification proposals to the MCC 'ecretar*. Comments are forwarded to Committee members with other agenda material before each meeting. Appro(imatel* si( wee8s is a)ailable for the preparation of comments. Closing dates are pro)ided on the web site. Although Medsafe will usuall* consult with companies li8el* to be affected b* a proposed reclassification+ companies should refer to the web site to determine whether an* of their products are li8el* to be affected. Medsafe ma* see8 ad)ice on classification matters+ where appropriate+ from e(perts or specialist organisations. Phase : Recommendation Bollowing each MCC meeting+ the confirmed minutes are forwarded to the Minister-s delegate. Phase 5: *ecision The Minister-s delegate accepts or declines the recommendations made b* the Committee. Phase 6: !ommunication Classification recommendations and proposed reclassifications are notified on the web site. Those who ha)e made submissions to the Committee recei)e indi)idual letters e(plaining the outcome. A period of four wee8sX ad)ance notice is pro)ided before changes are effected b* a notice in the Ga)ette# Phase 7: 1,<ection

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Notice of intention to obNect to a recommendation for reclassification should be lodged with the 'ecretar* b* the date gi)en on the web site. Appro(imatel* !2 wor8ing da*s are allowed. The obNection itself need not be lodged at this time but 6 copies+ including supporting data+ should be submitted to the 'ecretar* b* the closing date for the ne(t meeting. If a notice of intention to obNect is recei)ed+ the medicine is remo)ed from the draft Ga)ette list until the obNection is resol)ed. This is an opportunit* to obNect to the recommendation+ rather than to the initial proposal. =bNections must be made on the basis of new safet* data not a)ailable to the Committee at the time the recommendation was made. 'upporting safet* data should accompan* an obNection. Binancial or commercial reasons are not acceptable grounds for obNection. Medsafe considers the e)idence submitted in support of the obNection and will decide whether or not the matter should be referred bac8 to the MCC. Normall* obNections will be referred bac8 to the Committee onl* when there is substantial new safet* e)idence to support the obNection. Medsafe ad)ises the obNector of the outcome and gi)es the original applicant a chance to comment to the Committee about the obNection. Phase =: !onfirmation The Minister-s delegate signs a notice for publication in the Ga)ette to confirm those recommendations which ha)e not been the subNect of an obNection. Phase >: Notification Classification changes are effected b* notification in the Ga)ette# The* are subse;uentl* incorporated into the Birst 'chedule of the Medicines Regulations b* means of an amendment. Phase ?: $mplementation Bollowing a reclassification+ a change of labelling is usuall* necessar*. This re;uires the sponsor to submit a 'elf3assessable Change Notification. The legislation allows three months from the date of notification of a classification change for stoc8 labelled with the old classification to be replaced at wholesale le)el and si( months for replacement of stoc8 at retail le)el. Companies should contact Medsafe if the* are unable to meet these time3frames.

1:0;

'u*missions for Reclassification

'ubmissions to the MCC are usuall* made b* pharmaceutical companies+ health professional organisations or Medsafe. Indi)iduals or groups ma8ing submissions are ad)ised to liaise with the pharmaceutical companies who mar8et the medicines for which a change of classification is sought. A submission for the reclassification of a medicine should include& 6art A !. International Non3proprietar* Name or 1ritish Appro)ed Name or A' Adopted Name# of the medicine %. Proprietar* name s# :. Name of compan*.organisation.indi)idual re;uesting reclassification 4. Dose form s# and strength s# for which a change is sought 9. Pac8 si/e and other ;ualifications 7. Indications for which change is sought 5. Present classification of medicine 6. Classification sought ". Classification status in other countries especiall* Australia+ AG+ A'A+ Canada# !2. >(tent of usage in N, and elsewhere e.g. sales )olumes# and dates of original consent to distribute !!. 0abelling or draft labelling for the proposed new presentation s#

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!%. Proposed warning statements if applicable !:. =ther products containing the same acti)e ingredient s# and which would be affected b* the proposed change. 6art F Reasons for re;uesting classification change. This section should be supported where rele)ant b* the following& !. %. :. 4. 9. 7. 5. 6. ". A statement of the benefits to both the consumer and to the public e(pected from the proposed change >ase of self3diagnosis or diagnosis b* a pharmacist for the condition indicated Rele)ant comparati)e data for li8e compounds 0ocal data or special considerations relating to N, Interactions with other medicines Contraindications Possible resistance Ad)erse e)ents 3 nature+ fre;uenc* etc. Potential for abuse or misuse.

All claims made in a submission should be supported b* researched data. =nl* 8e* papers need be supplied. References are ade;uate for other material. The Committee does not ma8e recommendations to the Minister on moral or ethical matters or on financial matters other than in terms of access for consumer con)enience. >ight copies of each submission are re;uired. As copies of submissions need to be distributed to Committee members and filed at Medsafe+ it is preferable that the* are bound with a simple codafile pin. Do not use bul8* ring binders. 'piral binding is acceptable. In addition to the 6 paper copies of each submission re;uired b* Medsafe and the MCC+ please submit an electronic cop* in M' ?ord format# on a flopp* dis8. The electronic cop* should contain Parts A and 1 as specified abo)e. An e(ecuti)e summar* ma* also be included. Please do not send the supporting data in electronic cop*. An electronic cop* of the submission is re;uired+ as Parts A and 1 but not the supporting data# of all submissions since March %222 are published on Medsafe-s web site under KAgenda ItemsL. An* reports written for the MCC b* Medsafe are also published. 'ubmissions+ and all other communications on classification matters+ should be addressed to& The 'ecretar* Medicines Classification Committee Medsafe P= 1o( 92!: ?ellington

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'ection 1;:

(linical #rials of Medicines

Section summary "his section e>-lains how to a--ly for an e>em-tion from the Medicines :ct in order to conduct a clinical trial of a medicine# )ote" For the re uirements for clinical trials of medical de!ices see *ection 2#$ of these Guidelines# Legislation and guidelines to read in conjunction with this section" Medicines :ct 1&21, section '0C />em-tion for clinical trial New Zealand Regulatory Guidelines for Medicines# Volume 'C 9nterim Good %linical Research 1ractice Guideline A:ugust 1&&2B

1;01

&ntroduction

The Medicines Act !"6! defines the parameters and re;uirements for the sale+ manufacture and suppl* of medicines in New ,ealand. 'ection :2 of this Act describes the process that a stud* sponsor or manufacturer must follow to obtain an e(emption from sections %2 and %4 of the Act for medicines re;uired for use in clinical studies. 'ection :2 also describes the obligations of the sponsor for reporting ad)erse effects and progress to the Ministr* of <ealth during the course of the stud*. An e(emption is re;uired for in&estigational and co%parator medicines which& are new chemical entities NC>s# and.or are new or different dose forms+ deli)er* s*stems+ or formulations of established medicines+ which ha)e not been appro)ed for mar8eting in New ,ealand+

e(cept where the stud* is solel* designed to compare the bioa)ailabilit* of a new medicine with one which is currentl* mar8eted. A stud* designed solel* to compare bioa)ailabilit* of a new medicine with one with consent to distribute+ using health* )olunteers+ is not considered a clinical trial and does not re;uire an application for appro)al under section :2 of the Medicines Act. <owe)er+ ethics committee appro)al is still re;uired. Medicines for which consent to mar8et has alread* been granted do not re;uire a 'ection :2 e(emption when the stud* protocol proposes that the medicine is used for an indication which has not been appro)ed for the product in New ,ealand. The principal in)estigator must obtain appro)al of the stud* protocol and related documents from an ethics committee. The committee must be constituted and operated according to the National 'tandard of >thics Committees+ and be accredited b* the <ealth Research Council-s >thics Committee+ or the Director3General of <ealth+ as being ;ualified to re)iew clinical trials in)ol)ing human participants. The Director3General of <ealth ma* grant appro)al for use of a medicine in a clinical trial after recei)ing& a fa)ourable recommendation from the <ealth Research Council-s 'tanding Committee on Therapeutic Trials 'C=TT# about the safet* of the medication and the )alidit* of the stud* protocol+ and

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

appro)al from an accredited ethics committee for the stud* protocol.

All medicines distributed under the pro)isions of section :2 of the Medicine Act must be labelled OTo be used b* ;ualified in)estigators onl*- or words of similar meaning. It is the responsibilit* of the importer or manufacturer to ensure that the medicine is supplied onl* to an authorised in)estigator. Detailed re;uirements for clinical trials conducted in New ,ealand are outlined in the Medsafe publication entitled New Zealand Regulatory Guidelines for Medicines# Volume 'C 9nterim Good %linical Research 1ractice Guideline. An electronic cop* can be accessed at Medsafe-s web site http&..www.medsafe.go)t.n/#.

1;0+

A))lication for A))ro.al of a (linical #rial

'ection :2 of the Medicines Act !"6! re;uires that an* application for a clinical trial of a medicine whether appro)ed for distribution in New ,ealand or not# must be lodged b* or in the name of a person or compan* resident in New ,ealand. An o)erseas compan* wishing to carr* out a clinical trial of a medicine in New ,ealand needs to ha)e a New ,ealand3based subsidiar* or appoint a local indi)idual or compan* as its New ,ealand agent to act for it in New ,ealand as the sponsor for the clinical trial concerned. The New ,ealand subsidiar* or agent is the sponsor legall* responsible for the trial+ and is the KapplicantL when the Director General-s consent for the trial is being sought. ?here an o)erseas compan* or a local or o)erseas consultant acts on behalf of a New ,ealand sponsor in submitting an application+ a letter from the sponsor confirming the o)erseas compan*-s or consultant-s authorit* to act on the sponsor-s behalf+ for the specific clinical trial for which the application is made should be forwarded to Medsafe either with the application or separatel*. Point applications in which all or part of the data are shared+ ma* be made b* two or more sponsors. It should be clearl* indicated in the application that each sponsor supports the shared use of the data. This ma* be indicated b* the co)ering letter s# being signed b* all sponsors. The letter s# must identif* the person to whom ;uestions and other correspondence relating to the application should be addressed. An application for appro)al of a clinical trial should be made using the application form in New Zealand Regulatory Guidelines for Medicines# Volume 'C 9nterim Good %linical Research 1ractice Guideline. An electronic cop* can be accessed at Medsafe-s web site http&..www.medsafe.go)t.n/# =N> cop* of the completed application form+ with supporting data and application fee R%+622 incl. G'T#+ should be sent to the Manager+ Medsafe at the address gi)en in 'ection !.%& B=AR copies of the completed application form and supporting data should also be sent to the Chairperson of 'C=TT+ at the address gi)en in 'ection !.%. All subse;uent communication with the 'C=TT should be addressed through Medsafe. The Director3General of <ealth will ad)ise the applicant or the applicant-s representati)e# of the final outcome of the application within 49 da*s of its receipt. If the decision is to decline the application+ the reasons for declining will be pro)ided.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

'ection 1<:

6harmaco.igilance

Section summary New Zealand has an esta+lished and effecti!e -harmaco!igilance system for -ost4mar3eting sur!eillance of medicine use# "his includes the s-ontaneous ad!erse reactions re-orting scheme and an 9ntensi!e Medicines Monitoring 1rogramme# *-onsors ha!e a res-onsi+ility to ad!ise Medsafe of in!estigations of safety issues +y o!erseas regulatory authorities, and data warranting a change to a data sheet# Legislation to read in conjunction with this section Medicines :ct 1&21, *ection .1C 7uty of im-orter or manufacturer to re-ort untoward effects of medicines

1<01

')ontaneous Ad.erse Medicine Reaction Re)orting 'cheme

A )oluntar* ad)erse reaction reporting scheme for the monitoring of ad)erse reactions to medicines+ )accines and fractionated blood products occurring in New ,ealand is operated b* the Centre for Ad)erse Reactions Monitoring CARM# under the guidance of the Medicines Ad)erse Reactions Committee MARC#. New ,ealand now has the highest reporting rate of ad)erse medicine reactions of all member countries in the ?<= International Drug Monitoring programme. Prescribers and pharmacists are encouraged to report to CARM an* suspected reaction that is of clinical concern. In particular+ CARM is interested in recei)ing reports of& All suspected to reactions to new medicines All suspected interactions Reactions to an* medicines suspected of causing& 3 Death 3 Danger to life 3 Admission to hospital or prolongation of hospitalisation 3 Persisting disabilit* 3 'ignificant inter)ention to manage the reaction and pre)ent disabilit* 3 Absence from producti)e acti)it* 3 1irth defects All serious allergic reactions+ e)en if well 8nown All suspected ad)erse reactions listed in 1rescri+er <-date as :d!erse Reactions of %urrent %oncern# Postage paid reporting cards are distributed with each issue of the New /thicals %atalogue# Reporting guidelines are printed on the inside bac8 co)er of the Catalogue and are a)ailable on the web site. As well+ the reporting form can be downloaded from Medsafe-s web site http&..www.medsafe.go)t.n/#. A cop* of this reporting card is included in Appendi( !9. A separate reporting form is used to report ad)erse reactions to fractionated blood products. 0ocal blood centres suppl* these forms on re;uest. The reporting form can also be downloaded from Medsafe-s web site http&..www.medsafe.go)t.n/#. A cop* is included in Appendi( !7.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

1<0+

&ntensi.e Medicines Monitoring 6rogramme

A small number of medicines are monitored in the Intensi)e Medicines Monitoring Programme IMMP#. The* are usuall* no)el agents which are recommended for consideration for inclusion on the programme b* the Medicines Assessment Ad)isor* Committee. A medicine ma* also be monitored+ following a recommendation from the Medicines Ad)erse Reactions Committee+ if a safet* concern is identified after mar8eting. Practitioners are re;uested to report to CARM all ad)erse clinical e)ents occurring in patients recei)ing IMMP medicines whether or not the* are thought to be causall* related to the medicine concerned#. Pharmacists are re;uested to send in records of all dispensings of these medicines. The current list of medicines in the IMMP is published in each issue of New /thicals %atalogue and 1rescri+er <-date. 'ponsors should include a statement that the medicine is in the IMMP in all ad)ertising and promotional material and in the data sheet. 'i(3monthl* sales figures should be supplied to the Medical Director of the IMMP. Bollowing a recent re)iew of pharmaco)igilance in New ,ealand a new polic* and process for placing medicines on the IMMP has been adopted. These are as follows& 6olicy At least the first two members of a new class of medicine are considered for monitoring at the time of recommendation for appro)al for distribution in New ,ealand. This applies to all products recommended from ! 'eptember !""". In addition+ the MARC ma* recommend that a medicine is monitored in the IMMP because it has identified ;uestions or concerns which it belie)es could and should# be addressed b* monitoring. 6rocess The process is as follows& +tep 1 The recommendation for monitoring is recei)ed b* Medsafe which then ad)ises the sponsor compan* of the recommendations and the subse;uent process for deciding whether monitoring should proceed+ and encourages the sponsor compan* to participate in the process. +tep 2 The Director of the IMMP prepares a feasibilit* stud* for monitoring and submits it to Medsafe within 6 wee8s of the initial recommendation. >ach stud* will include a monitoring methodolog* and a discussion of the merits of monitoring the medicine compared with other candidates for monitoring. The Director will de)elop this stud* in consultation with the sponsor compan* and pro)ide a cop* of the feasibilit* stud* to the sponsor. 'ponsor companies ma* pro)ide a separate opinion.report on the merits of monitoring as an appendi( to the Director-s report. +tep The feasibilit* stud* is considered b* an IMMP ad)isor* panel which ad)ises Medsafe whether it recommends proceeding with monitoring of the product. The panel members are the 'enior Medical Ad)isor to Medsafe+ the Director of the IMMP+ and the Chairpersons of the MAAC and MARC. The panel will ma8e its recommendation within 4 wee8s of recei)ing the Director-s report. +tep 5 Medsafe decides whether monitoring should proceed and ad)ises the sponsor compan* and the CARM of its decision. 'ponsor companies will be supplied with a cop* of an* material rele)ant to the decision. A))eal mechanism

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

The onl* grounds for appeal are that matters rele)ant to the decision ha)e not been considered. Appeals+ with supporting information+ ma* be lodged with Medsafe within !4 da*s of the letter from Medsafe ad)ising of the decision to monitor the medicine. Appeals will be considered b* the MARC. !uration and funding of monitoring A re)iew of the need for continued monitoring will occur % *ears after the commencement of monitoring and annuall* thereafter. Monitoring will be funded b* Medsafe.

1<03

Res)onsi*ility of (om)anies to Re)ort Ad.erse Medicine Reactions


Re)orting ad.erse reactions to (ARM

1<0301

Prescribers or pharmacists informing sponsors of serious or une(pected ad)erse medicine reactions occurring in New ,ealand should be encouraged to report cases directl* to CARM. <owe)er+ the sponsor should report cases directl* if the* consider the prescriber or pharmacist is unli8el* do so. In these instances+ the reporting card should be completed and forwarded to CARM at the following address& The Medical Assessor Centre for Ad)erse Reactions Monitoring P= 1o( "!: Dunedin Telephone U74 2: 45" 5!69 Ba( U74 2: 455 292"

1<030+

Re)orting su*stantial untoward effects of medicines

'ection 4! of the Medicines Act re;uires medicine manufacturers or importers to report to the Director3 General an* substantial untoward effects of their medicines that ha)e arisen at an* time+ whether in New ,ealand or o)erseas. In practical terms+ this means that Medsafe should be informed promptl* of an in)estigation of a safet* issue b* an o)erseas regulator* authorit* and.or an* safet* information necessitating a change in the data sheet. Information on in)estigations of safet* issues and data warranting a change in a data sheet should be forwarded to& The 'ecretar* Medicines Ad)erse Reactions Committee Medsafe P= 1o( 92!: ?ellington Copies of indi)idual ad)erse reaction case reports recei)ed from o)erseas countries should not be forwarded to CARM or Medsafe+ but should be retained b* the compan*. 0i8ewise+ Medsafe should not routinel* be sent Periodic 'afet* Apdate Reports P'ARs#. <owe)er+ these should be held b* the sponsor+ and ma* be re;uested if a safet* issue warrants re)iew b* Medsafe. In addition+ a sponsor ma* include a recent P'AR in a submission to Medsafe on a safet* issue.

1<0303

Media interest in medicine safety issues

Medsafe should be informed promptl* of an* interest b* the local or o)erseas media in a medicine safet* issue. This enables Medsafe to in)estigate the issue using New ,ealand data and prepare a

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

response to the New ,ealand media that a)erts an* unnecessar* speculation and concern amongst the public and prescribers.

1<05

(entre for Ad.erse Reactions Monitoring -(ARM/

CARM processes all reports of ad)erse reactions and enters the information into its database. A response+ with comment on the case+ is sent to the reporter. After the reports ha)e been assessed using the ?<= causalit* and se)erit* criteria and the reaction designated using the ?<= terminolog*+ CARM transmits ad)erse reaction reports to the ?<= Collaborating Centre for International Drug Monitoring in Appsala+ 'weden. This information adds to the international database of ad)erse reactions to medicines. Pharmaceutical companies can purchase ad)erse reaction reports for an* medicine from CARM. Companies can arrange for customised reports on named medicines to be sent to them on a regular basis multiples of ;uarters#. There is an initial set3up fee for the customisation which includes an historical printout of ad)erse reactions to date. >ach printout thereafter incurs a fee.

1<08

Medicines Ad.erse Reactions (ommittee

The Medicines Ad)erse Reactions Committee MARC# is a ministerial ad)isor* committee of general practitioners and medical specialists. MARC o)ersees the spontaneous ad)erse reaction reporting scheme and the IMMP+ re)iews ad)erse reaction data published in the medical literature and ad)ises the Minister and Medsafe on issues relating to the safet* of medicines+ including information to be disseminated to prescribers and pharmacists.

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

A))endi1 1:

'chedule of Fees

!5:

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

'chedule of Fees
The fees appl*ing to the )arious t*pes of applications and notifications are listed below Application for consent to distribute a new medicine incl. a new combination product# containing a new acti)e pharmaceutical ingredient I1$93,, for ! strength of ! dose form plus additional fees for an* additional names.dose forms.strengths.fla)ours 'ee NMA form for details# Application for consent to distribute a new multi3source prescription or =TC medicine containing one or more acti)e ingredients I79.,, for ! strength of ! dose form plus additional fees for an* additional names.dose forms.strengths.fla)ours. 'ee NMA form for details# Application for consent to distribute a new name+ dose form+ strength+ classification or fla)our of a currentl* distributed medicine or related product or a new combination pac8 containing two or more currentl* distributed medicines 'ee rele)ant NMA or NRPA form for details# Application for consent to distribute a new related product I $9$,, plus additional fees for an* additional names.dose forms.strengths.classifications.fla)ours. 'ee NRPA form for details# Application for pro)isional consent to distribute a new medicine I $9,,, Application for renewal of pro)isional consent I $,, Plus an additional fee of R%22 for each additional name.dose form.strength.fla)our# Material change s# 'ee CMN or CRPN form for details# 'elf3assessable change s# Note: No fee is pa*able if a self3assessable change s# is notified at the same time as another assessable change s# for which a CMN or CRPN fee is pa*able. Application for consent to conduct a clinical trial I 29.,, Appeal to the Medicines Re)iew Committee I /9,,, Issue of a Certificate of Pharmaceutical Product I 2$, Bor each name+ dose form+ strength and fla)our of each product and each countr* for which a certificate is re;uired.# I 2,, Bor an* number of self3 assessable changes to a single product or data sheet#

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

A))endi1 +:

NMA Form

!59

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

NEW ME!&(&NE A66 &(A#&$N


2including additional name dose form strength or flavour4
#his form is to be used when applying for consent to distribute a new medicine including a product that is substantially the same as an approved parent product but differs from the parent product in name dose form strength or flavour" One copy of the form must be completed for each separate product 2name / dose form / active ingredient2s4 / strength / classification / flavour as applicable of a medicine4" )o not use this form for a new related product application" 6nstead use the separate 7'8$ 9orm

'ection 1:
#rade name: !ose form:

Administrati.e data

101 6ro)osed )roduct details

:;ee Guidelines for acceptable terms<

Acti.e ingredient-s/:
:-se 677 and also give C$; 7umber for new chemical entities<

'trength: Route of administration: 6harmacothera)eutic grou):


:e"g" $ntibacterial )iuretic Vaccine<

10+ #y)e of )roduct


(tick one)

#y)e & #y)e &&

ower=ris2 medicines &ntermediate= or 7igher=ris2 medicine other than *iological or *iotechnological )roducts -*ut including anti*iotics and li2e su*stances deri.ed from micro=organisms/ Fiological or *iotechnological )roducts -i0e0 .accines> serums and allergens> medicinal )roducts deri.ed from human *lood or )lasma> immunological medicinal )roducts> and )roducts deri.ed from *iotechnology/

#y)e &&&

103

egal classification
(tick one)

(ontrolled !rug:

(lass =======

6rescri)tion medicine Restricted -6harmacist $nly/ medicine 6harmacy=$nly medicine General sales medicine Not yet classified

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

105 6roduct )ac2aging> )atient information and shelf=life


(ontainer> closure ty)e and administration de.ice: 6ac2 si@e-s/ to *e registered in New Zealand: A )atient information leaflet is to *e su))lied with the )roduct in New Zealand: 2>es07o4 #he )atient information leaflet is to *e )u*lished as (onsumer Medicine &nformation -(M&/:
2>es07o4

6ro)osed shelf=life and storage conditions:

Unopened: Opened: Reconstituted:

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

108

Manufacturing> )ac2ing and testing details

#0 "anufacturer%s& of active ingredient%s& Name of ingredient: Name of manufacturer: Address of site of manufacture: GM6 (ertification -if a.aila*le/ issued *y: !ate of &ssue: !rug Master File and Aletter of accessB su*mitted: >es 0 7o
:6f )!9 previously submitted give !edsafe 9ile 7o2s4" 7ote that a new letter of access may be re,uired"<

##9,= ????"??? ##9,= ????"??? (ertificate of 'uita*ility -with Aletter of accessB/ su*mitted in lieu of !MF: 2>es07o4 /0 "anufacturer%s& of finished product Name of manufacturer: Address of site of manufacture: GM6 (ertification issued *y: !ate of &ssue: Manufacturing ste)s carried out at this site:

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

!0 Packer%s& of finished product Name of )ac2er: Address of site of )ac2ing: GM6 (ertification issued *y: !ate of &ssue: 6ac2aging ste)s carried out at this site:
2e"g" primary packaging secondary0outer packaging labelling overlabelling4

*0 +ite%s& responsi,le for testing of finished product and ,atch release Name of site: Address:

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

109

6roduct com)osition
Iuantity Iuality standard
:8h @ur 0 A8 0 -; 0 Bouse<

Name of ingredient Active(s): Excipients:

10: #ransmissi*le ')ongiform Ence)halo)athy 'tatus


Cist any ingredients of animal origin included in the formulationD

Cist any ingredients of animal origin with which the product comes in contact during its manufactureD

#'E !eclaration:
(tick one)

;he product contains no ingredients derived from animals0 $f applica,le- any stearate or stearic acid in the product is derived from a vegeta,le source0 ;he product contains %or comes into contact during its manufacture& with animal8 derived materials that are potential sources of ;+E agents ,ut appropriate precautions are taken in accordance with the European !ommission and 3+ 'ood and *rug #dministration re9uirements to minimise the risk of contamination with ;+E agents0

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

10; Regulatory status #0 1verseas applications and approvals


Name of regulatory authority @uropean !edicines @valuation $gency
2@- Centralised 8rocedure4

!ate of a))lication

A))lication status
2incl" dates of any approvals4

26ndividual @uropean country agency4

27ational approval procedure or @- !utual 'ecognition 8rocedure4D

$ustralian #G$ Canadian Bealth 8roduct and 9ood Aranch -; 9)$

/0 New Zealand Environmental Risk "anagement #uthority %ER"#&


6ndicate if the product re,uires @'!$ consent for import and use in 7ew Eealand and if so when an application was lodged with @'!$ and the status of the application" 2;ee ;ection 2"11"2 of New Zealand Regulatory Guidelines or !edicines "olu#e $ for details of re,uirements"4

#his )roduct is a ha@ardous su*stance or a new organism in terms of the 7a@ardous 'u*stances and New $rganisms legislation and re?uires a))ro.al from ERMA *efore *eing released in New Zealand

>es 0 7o

26f >es4 $n application for consent was lodged with @'!$ on 2date4D ???????? &f an a))lication has *een lodged with ERMA> has a))ro.al *een gi.enC >es 0 7o

26f >es4 #he @'!$ $pproval Code isD ??????????????????""??"

!6!

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

10<

ist of attached documents !ocumentation


#ick if included or mark F70$G

Administrati.e !ata:
)etailed table of contents for the dossier of technical data
Kmust *e includedL

)raft label2s4 and Cabelling )eclaration2s4


8atient 6nformation Ceaflet08ackage 6nsert )raft data sheet checklist and declaration

KA full si@e co)y or a full si@e draft indicating colours for each )rimary and secondary la*el> and a com)leted chec2 list for each la*el> and a signed a*elling !eclaration co.ering all of the la*els must *e su))lied0L Kif a))lica*leL Kif a))lica*leL Kif a))lica*leL Kif a))lica*leL

Good !anufacturing 8ractice documentation #abular summary of subHects in clinical trials


Kif a))lica*leL

8h @ur Certificate2s4 of ;uitability for active ingredient2s4 with letter2s4 of access Copies of evaluation reports from overseas regulatory authorities
Kif a.aila*leL

Copies of company responses to issues raised by overseas regulatory authorities where relevant to 7ew Eealand re,uirements Kif a.aila*leL Completed check list for completeness of chemical pharmaceutical biological and bioavailability data package Kmust *e included for a new multi=source -generic/
)rescri)tion medicine0 Not re?uired for a new inno.ati.e medicine or a new lower ris2 medicineL

#echnical !ata:
:6CB Common #echnical )ocument 2C#)4 format !odules 25+ or @- format 8arts 6C I 6V<

C#) !odule 2 Overviews and ;ummaries or @- format @Jpert 'eports


Kif a.aila*leL

7o of VolsD ====== Chemical pharmaceutical and biological documentation


:C#) !odule K or @- format 8art 66<

7o of VolsD ====== #oJicological and pharmacological 2pre5clinical4 documentation


:C#) !odule ( or @- format 8art 666<
Kif a))lica*leL

7o of VolsD ====== Clinical )ocumentation


Kif a))lica*leL

:C#) !odule ( or @- format 8art 666<

7o of VolsD ====== )rug !aster 9ile2s4 with letter2s4 of access


Kif a))lica*leL

7o of VolsD ====== 8lasma !aster 9ile2s4 with letter2s4 of access Aioe,uivalence study report2s4
Kif a))lica*leL Kif a))lica*leL

7o of VolsD ====== 7o of VolsD ====== #otal num*er of .olumes of data su*mitted:

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

101, Fee calculation


#ick one boJ in the left hand column beside the appropriate type of application" Copy the amount from the corresponding F9eeG boJ to 8art 1"11 F$pplication fee enclosedG below4

2%ick one &ox only)

#y)e of a))lication 7ew medicine containing one or more new active substances 7ew medicine that does not contain a new active substance 7ew medicine 5 8rovisional consent 7ew medicine 5 'enewal of 8rovisional consent $dditional name 5 Grade 1 $dditional name 5 Grade 2 $dditional classification 2with0without new name4 $dditional strength 5 Grade 1 $dditional strength 5 Grade 2 $dditional strength 5 Grade K $dditional strength 5 Grade ( $dditional strength 5 Grade + $dditional flavour or type of sweetening $dditional dose form 5 Grade 1 $dditional dose form 5 Grade 2 7ew combination pack containing 2 or more currently approved products

Fee -M/ 18>3,, :>;,, 8>,,, 8,, 5,, ;,, 5,, ;,, 1>9,, 3>+,, 3>+,, 5>;,, ;,, 5>;,, 9>5,, 1>9,,

1011 A))lication fee )aid: M NNNNNNNNN 0,, 101+ Method of )ayment:


Che,ue enclosed )irect credit 2details enclosed4

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

1013 A))licantD')onsor details and declaration


$n accordance with the "edicines #ct 1?>1 and the "edicines Regulations 1?>5$ here,y apply for consent to distri,ute in New Zealand the product descri,ed a,ove0 $ certify that the information supplied is complete and correct to the ,est of my knowledge and that no relevant information has ,een omitted0 Name> designation and address of )erson su*mitting the a))lication:
:$ll correspondence relating to the application will be sent to this person unless otherwise re,uested"<

Email address:

'ignature: ==================================== !ate: =================== ')onsor name and address:

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

'ection +: differences

&dentification

of

)arent

)roduct

and

Complete this section only if this application is for consent to distribute an additional name dose form strength flavour or classification of an eJisting parent product" Otherwise submit only ;ection 1" 6f the category of difference2s4 is0are not clearly covered by one of the categories in the table in ;ection 2"2 please contact !edsafe for guidance before submitting the application and fee"

+01 &dentification of )arent )roduct


#his a))lication is for consent to distri*ute a new )roduct that is su*stantially similar to the following )arent )roduct: 6arent )roduct-s/ name-s/: !ose Form: 'trength: Medsafe File Ref0 ##+05

(omments:

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New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

+0+ !ifferences *etween )arent )roduct and new )roduct


#ick the boJ below that best describes the difference2s4 between the new and parent products" 6f appropriate describe the similarities and differences between the new and parent products in greater detail under FCommentsG in section 2"1 of the form" (%ick one)

!ifference *etween )arent )roduct and new )roduct


Additional name = Grade 1
new name to be used in addition to eJisting name all other details identical to )arent )roduct eJcept for labelling new label displays new name but all other information on the label is essentially the same as on the parent product label 2even if layout is different4 new name to be used in addition to eJisting name all other details identical to )arent )roduct eJcept for labelling new label displays new name layout of label may be different from that of parent product some other information on the label is different from that on the parent product label new classification to be used in addition to eJisting classification 2with or without a new name4 all other details identical to )arent )roduct eJcept for labelling new label displays new classification 2and new name pack siLe indications dosage instructions if applicable4 new and parent products have the same dose form new product is a direct scale of parent product or uses same eJcipient matriJ all other details identical to )arent )roduct eJcept for labelling and specifications new and parent products have the same dose form new product is not a direct scale of parent product bioe,uivalence study not re,uired all other details identical to )arent )roduct eJcept for labelling and specifications new and parent products have the same dose form new product is not a direct scale of parent product bioe,uivalence study not re,uired other details different from parent product new and parent products have the same dose form new product is not a direct scale of parent product bioe,uivalence study included all other details identical to )arent )roduct eJcept for labelling and specifications new and parent products have the same dose form new product is not a direct scale of parent product bioe,uivalence study included other details different from parent product new and parent products have the same dose form new product has a fla.our or ty)e of sweetening different from the parent product all other details identical to )arent )roduct eJcept for labelling 2if applicable4and specifications new and parent products have different dose forms and the same or different strengths bioe,uivalence not relevant to new dose form new and parent products have different dose forms and the same or different strengths bioe,uivalence study or clinical data included new combination pack containing two or more currently approved finished products primary packaging for each component unchanged or any change does not affect stability0shelf5life

Additional name = Grade +

Additional classification

Additional strength = Grade 1

Additional strength = Grade +

Additional strength = Grade 3 Additional strength = Grade 5

Additional strength = Grade 8 Additional fla.our or ty)e of sweetening

Additional dose form = Grade 1 Additional dose form = Grade + New com*ination )ac2

(End o or#)

!67

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

A))endi1 3:

NR6A Form

!65

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

NEW RE A#E! 6R$!"(# A66 &(A#&$N


2including additional name dose form strength or flavour4
#his form is to be used when applying for consent to distribute a new related product including a product that is substantially the same as an approved parent product but differs from the parent product in name dose form active ingredient strength or flavour" One copy of the form must be completed for each separate product 2name / dose form / active ingredient2s4 / strength / flavour as applicable of a related product4"

'ection 1:

Administrati.e data

101 6ro)osed )roduct details


#rade name: #y)e of 6roduct:
:e"g" $nti5dandruff shampoo fluoride toothpaste antiseptic throat loLenge<

Acti.e ingredient-s/: 'trength: (ontainer and closure ty)e: 6ac2 si@e-s/ to *e registered in New Zealand: 6ro)osed shelf=life and storage conditions:
:if applicable<

10+

Manufacturing and )ac2ing details

Name of manufacturer: Address of site of manufacture:

Name of )ac2er: Address of site of )ac2ing:

!66

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

103

6roduct com)osition
Iuantity Iuality standard
:8h @ur 0 A8 0 -; 0 Bouse<

Name of ingredient Active(s): Excipients:

105

ist of attached documents !ocumentation


#ick if included or mark F70$G

Administrati.e !ata:
#able of contents
Kmust *e includedL

)raft label2s4 and Cabelling )eclaration2s4 (hemical and 6harmaceutical !ata:


Composition and 8resentation of 8roduct !ethod of 8reparation ;pecifications for $ctive 6ngredient2s4 ;pecifications for 9inished 8roduct ;tability Other 6nformation

KA full si@e co)y or a full si@e draft indicating colours for each )rimary and secondary la*el> and a com)leted chec2 list for each la*el> and a signed a*elling !eclaration co.ering all of the la*els must *e su))lied0L

!6"

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

108 Fee calculation


#ick one boJ in the left hand column beside the appropriate type of application" Copy the amount from the corresponding F9eeG boJ to 8art 1"11 F$pplication fee enclosedG below4

2%ick one &ox only)

#y)e of a))lication 7ew related product $dditional name 5 Grade 1 $dditional name 5 Grade 2 $dditional strength $dditional flavour or type of sweetening

Fee -M/ 8>8,, 5,, ;,, ;,, ;,,

109 A))lication fee )aid: M NNNNNNNNN 0,, 10: Method of )ayment:


Che,ue enclosed )irect credit 2details enclosed4

10; A))licantD')onsor details and declaration


$n accordance with the "edicines #ct 1?>1 and the "edicines Regulations 1?>5$ here,y apply for consent to distri,ute in New Zealand the product descri,ed a,ove0 $ certify that the information supplied is complete and correct to the ,est of my knowledge and that no relevant information has ,een omitted0 Name> designation and address of )erson su*mitting the a))lication:
:$ll correspondence relating to the application will be sent to this person unless otherwise re,uested"<

Email address:

'ignature: ==================================== !ate: =================== ')onsor name and address:

!"2

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

'ection +: differences

&dentification

of

)arent

)roduct

and

Complete this section only if this application is for consent to distribute an additional name dose form strength flavour or classification of an eJisting parent product" Otherwise submit only ;ection 1" 6f the category of difference2s4 is0are not clearly covered by one of the categories in the table in ;ection 2"2 please contact !edsafe for guidance before submitting the application and fee"

+01 &dentification of )arent )roduct


#his a))lication is for consent to distri*ute a new )roduct that is su*stantially similar to the following )arent )roduct: 6arent )roduct-s/ name-s/: !ose Form: 'trength: Medsafe File Ref0 ##+05 (omments:

+0+ !ifferences *etween )arent )roduct and new )roduct


#ick the boJ below that best describes the difference2s4 between the new and parent products" 6f appropriate describe the similarities and differences between the new and parent products in greater detail under FCommentsG in section 2"1 of the form" (%ick one)

!ifference *etween )arent )roduct and new )roduct


Additional name = Grade 1
new name to be used in addition to eJisting name all other details identical to )arent )roduct eJcept for labelling new label displays new name but all other information on the label is essentially the same as on the parent product label 2even if layout is different4 new name to be used in addition to eJisting name all other details identical to )arent )roduct eJcept for labelling new label displays new name layout of label may be different from that of parent product some other information on the label is different from that on the parent product label new and parent products have the same dose form new product is a direct scale of parent product or uses same eJcipient matriJ all other details identical to )arent )roduct eJcept for labelling and specifications new and parent products have the same dose form new product has a fla.our or ty)e of sweetening different from the parent product all other details identical to )arent )roduct eJcept for labelling 2if applicable4and specifications

Additional name = Grade +

Additional strength

Additional fla.our or ty)e of sweetening

(End o or#)

!"!

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

A))endi1 5:

(hec2list for New Multi=source Medicine !ata

!"%

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

(7E(H &'# F$R NEW M" #&='$"R(E ME!&(&NE A66 &(A#&$N !$''&ER
6roduct: ????????????????????????????
Where any re?uired information is not su))lied> the omission must *e e1)lained and Justified in a co.ering letter

2#ick as applicable4

6ro.ided

NDA

($M6$'&#&$N
1" Composition of the medicinal product #he com)osition of each product and strength is clearly defined" #he function of each e1ci)ient is defined and Hustified or obvious" 27oteD #he functions of the eJcipients may sometimes be found in ;ection 66$"(D F)evelopment 8harmaceuticsG"4 6f starch is used the source 2e"g" wheat maiLe rye barley oat4 is indicated" 6f more than one strength of a product is to be marketed it is clear how the different strengths are distinguished 2e"g" by differences in siLe colour shape markings etc"4

2" Container 2brief description4 #he )rimary -immediate/ and secondary -outer/ )ac2aging and packaging materials 2e"g" type of glass or plastic4 pack siLes any dosing device and any desiccant or cotton wool contained in the package are defined" 6f a desiccant is included in the package this is labelled with a warning such as F7ot to be takenG" 6f 7E !edicines 'egulations re,uire the product to be in a safety container it is so packaged" $ny induction seal or tamper proof seal is ade,uately defined"

K" Clinical trial formula2e4 #here is a clear indication of any differences between the formulation2s4 intended for marketing and that 2or those4 used in bioe,uivalence and0or clinical studies" (" )evelopment pharmaceutics #he Justification for the choices of salt isomer and stereoisomer0 racemate of the active substance the dose form2s4 formulation2s4 and manufacturing processes sterilising processes any overages and the packaging are self5evident or have been Hustified"
6ro.ided NDA

!":

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

ME#7$! $F MAN"FA(#"RE
10 Manufacturing formula #he *atch formula has been supplied for each strength of each dose form" 6n each case the *atch si@e-s/ has been defined in terms of total mass0volume and number of units produced" #he ?uantities of the indi.idual ingredients correspond to those claimed for the unit composition and there are no uneJplained or hidden overages" $ny o.erage-s/ of acti.e ingredient-s/ has been Hustified" 6f ranges are given for ,uantities of eJcipients these have been Hustified and validated" $ny o.erfill of the container-s/ has been Hustified" )etails 2incl" ,uantities and ,uality standards4 have been provided for any sol.ents used but removed in the process" )etails 2including ,uality standards4 have been provided for any gases used in the process or used to fill the headspace in the product container"

+0 Manufacturing )rocess @ach manufacturing> sterilisation -if a))lica*le/ and )ac2aging )rocess and the e,uipment used has been described" 6f alternati.e )rocesses are intended at some steps in the manufacture or at different manufacturing sites these have been Hustified and shown to yield product of e,uivalent ,uality" #he in=)rocess controls 2incl" #emperatures miJing times and speeds completeness of sterilisation of e,uipment and product test methods and acceptance limits at each step4 are defined" 6f relevant any )rocessing -e0g0 washing> sterilisation/ of the containers before filling is described"

30 Validation of the manufacturing )rocess )etailed validation data have been provided for all critical ste)s in the manufacturing process 2including any cleaning and0or sterilisation steps4" Validation data have been generated at each manufacturing site involved in the production of the product" Validation data have been generated at either )roduction scale or at )ilot scale 210M of full scale or 100 000 solid dose units whichever is the greater unless otherwise Hustified4 using production scale e,uipment or in the case of the production scale being less than 100 000 units at production scale" 6f only )ilot scale .alidation has been completed full scale validation is scheduled for when commercial scale production commences"

!"4

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

6ro.ided

NDA

($N#R$ $F '#AR#&NG MA#ER&A '


10 Acti.e su*stance-s/ $ complete !MF2s4 and accompanying Aletter of accessB 2or a 8h @ur Commission F(ertificate of 'uita*ility G in lieu of a )!94 has been submitted in support of this 7!$ 2or a previous 7!$4 for each manufacturer of *ul2 acti.e" #he full s)ecifications a))lied to the *ul2 acti.e ingredient *y the finished )roduct manufacturer are provided" 6f the specifications are non=)harmaco)oeial all of the testing procedures and re,uirements are described in detail" 6f certain tests are not carried out routinely Hustification has been provided" Validation data have been provided for all assay tests 2whether pharmacopoeial or not4 and the data cover 2as applicable4D
1" 2" K" (" +" N" *" specificity or selectivity accuracy 2agreement with true value4 intra5assay precision intra5laboratory inter5assay repeatability linearity stability of solutions robustness0ruggedness"

Validation data have been provided for all related )roductD degradation )roduct tests 2whether pharmacopoeial or not4 and the data cover 2as applicable4D
1" 2" K" (" +" N" *" &" %" specificity or selectivity limit of detection 2CO)4 limit of ,uantification 2COO4 accuracy 2agreement with true value4 intra5assay precision inter5assay repeatability linearity stability of solutions robustness0ruggedness"

Validation data have been provided for all residual sol.ent tests 2whether pharmacopoeial or not4 and the data cover 2as applicable4D
1" 2" K" (" +" N" *" &" %" specificity or selectivity limit of detection 2CO)4 limit of ,uantification 2COO4 accuracy 2agreement with true value4 intra5assay precision inter5assay repeatability linearity stability of solutions robustness0ruggedness"

Validation data 2or at least evidence of system suitability4 have been provided for all micro*iological tests 2whether pharmacopoeial or not4 Where two or more testing laboratories are involved evidence has been provided that the test procedures have been ade,uately validated at each site" Fatch analytical data generated by the finished product manufacturer2s4 have been supplied for typical batches of bulk active substance from each supplier"

!"9

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

6ro.ided

NDA

2" @Jcipient2s4 )etails of the ,uality standards applied to each of the e1ci)ients 2including capsule shells commercial pre5miJed coating materials and any gases used in filling vials and ampoules4 have been provided" @vidence that ade,uate measures are taken to ensure that any ingredients of animal origin 2e"g" gelatin magnesium or calcium stearate stearic acid4 used in the product are free from #;@ contamination has been provided" 'epresentative *atch analytical data are provided for any e1ci)ients controlled *y non=)harmaco)oeial s)ecifications " :Note: 'atc( data are not nor#ally re)uired or co##only used excipients controlled &y p(ar#acopoeial speci ications*<

30 6ac2aging material -immediate )ac2aging/ #he materials used 2polymers types of glass etc"4 construction> dimensions and )hysical )ro)erties for containers any induction seals closures and any delivery device are defined" #he full s)ecifications and routine tests on the proposed marketing containers and closures are provided" @vidence has been provided to confirm that )lastic and ru**er packaging components are free from leachable toJic impurities and comply with the 8h @ur and -;8 re,uirements for polymeric materials used in packaging of medicines" 'epresentative *atch analytical data have been supplied for each container closure packaging material and delivery device 2if any4"

($N#R$ #E'#' $N &N#ERME!&A#E 6R$!"(#'


;pecifications and representative batch analytical data are provided for any intermediate product"

($N#R$ #E'#' $N #7E F&N&'7E! 6R$!"(#


10 ')ecifications and Routine #ests #he full s)ecifications for the finished product are provided" $ny non=)harmaco)oeial test procedures used as replacements for or in addition to the procedures in the pharmacopoeial monograph have been eJplained and Hustified" 6n any in house s)ecifications supplied it is clear which re,uirements apply at release and which apply throughout the shelf5life" 6f all s)ecified tests are not carried out routinely acceptable Hustification is given" 6f the product is tested in more than one test la*oratory there is an indication of whether the test procedures are the same in each laboratory or if there are any differences these have been defined and Hustified"

!"7

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

6ro.ided

NDA

($N#R$ #E'#' $N #7E F&N&'7E! 6R$!"(# -cont4d/


+0 'cientific !ata #he test procedures have been .alidated at each testing site intended for routine ,uality control of the product" Where two or more testing laboratories are involved evidence has been provided that the test procedures have been ade,uately validated at each site" Validation data have been provided for all assay tests 2whether pharmacopoeial or not4 and the data cover 2as applicable4D
1" 2" K" (" +" N" *" specificity or selectivity accuracy 2agreement with true value4 intra5assay precision inter5assay repeatability linearity stability of solutions robustness0ruggedness"

Validation data have been provided for all related )roductD degradation )roduct tests 2whether pharmacopoeial or not4 and the data cover 2as applicable4D
1" 2" K" (" +" N" *" &" %" specificity or selectivity limit of detection 2CO)4 limit of ,uantification 2COO4 accuracy 2agreement with true value4 intra5assay precision inter5assay repeatability linearity stability of solutions robustness0ruggedness"

Validation data have been provided for the assay method used to monitor dissolution and the data cover 2as applicable4D
1" 2" K" (" +" N" *" specificity or selectivity accuracy 2agreement with true value4 intra5assay precision inter5assay repeatability linearity stability of solutions robustness0ruggedness"

Validation data 2or at least evidence of system suitability4 have been provided for all micro*iological tests 2whether pharmacopoeial or not4 2e"g" sterility microbial counts abnormal toJicity endotoJins4 have been provided" :7oteD Validation of C$C tests is formulation5specific and must be repeated if any change is made to the formulation"< Validation data have been provided for any other test )rocedures 2whether pharmacopoeial or not4 that are not self5validating" Recent com)lete analytical re)orts 2in tabular form or as signed certificates of analysis4 have been included for each strength of each dose form of the final market formulation2s4 of the product manufactured at least at pilot scale on production scale e9uipment at each of the proposed manufacturing sites" 9or each batch reported the *atch num*er the date of manufacture the *atch si@e and the *atch num*erDcode for the *ul2 acti.e ingredient-s/ used in manufacture have been provided"

!"5

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

6ro.ided

NDA

'#AF& &#%
10 'ta*ility #ests on Acti.e 'u*stance-s/ :7ormally included in the )!9 if applicable< 'ta*ility #ests on the Finished 6roduct #he shelf=life s)ecifications are provided 2or referenced4 $ll of the test )rocedures have been defined" $ny non=)harmaco)oeial test procedures used as replacements for or in addition to the procedures in a pharmacopoeial monograph have been Hustified" $ny differences *etween test )rocedures for the shelf5life and release specifications have been Hustified and validated" #he stability data cover at least 1+ months storage at 2or above4 the recommended maJimum storage temperature" #he sta*ility trials were carried out in accordance with 6CB guidelines unless otherwise Hustified" #he dates on which the stability batches were manufactured and the dates on which they were placed on stability trial have been reported" #he trials were carried out using the )ro)osed mar2eting formulation of the product 2or formulations that may reasonably be eJpected to have the same stability4" Where there is only one strength0potency at least 3 *atches of the product were included in the trial" #wo of these should be at least pilot scale 2the other may be smaller if Hustified4" Where different strengthsD)otencies are direct scales at least 2 pilot scale batches of the highest and lowest strengths0potencies were included or where different strengths0potencies of the medicine are not direct scale5ups at least 2 pilot scale batches of each strength0potency were included in the trial" 6f the trials used )ilot=scale *atches trials using production5scale batches have commenced or are scheduled" 6f the product is manufactured at more than one manufacturing site *atches from each manufacturing site were included in the stability trials or data are to be generated for batches manufactured at the omitted site2s4" Aatch numbers or codes are reported for the *atches of acti.e su*stance used in the manufacture of the finished product used in the stability trials" #he )ac2aging for the stability batches is clearly defined" @ach of the )ro)osed local mar2eting containers 2or acceptable e,uivalents or less protective packagings4 was among those used in the trials"

+0

!"6

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

6ro.ided

NDA

'ta*ility #ests on the Finished 6roduct -cont4d/


6t is clear whether or not the real time stability samples were stored )rotected from light 2e"g" in the outer cartons4" 6n the case of li,uid products in a stoppered container the orientation of the primary containers 2e"g" upright and0or inverted4 is clearly indicated" 6f relevant )hotosta*ility has been investigated in accordance with 6CB Guidelines" #he storage tem)eratures and relati.e humidities used in the trials are defined" $ll of the test procedures have been .alidated in the laboratory used to analyse the stability samples" 6f there were any changes in test )rocedures during the course of the trials there has been comparison and correlation of results generated by the alternative methods" #he assay methods used for active substance and degradation products have been .alidated as sta*ility indicating " 6f relevant transmission of moisture in0out of the container has been investigated" 6f relevant leaching of su*stances from )lasticDru**er containers or closures has been investigated" 6f relevant )reser.ati.e le.els 2or effectiveness4 were monitored" 6f the data do not co.er the whole of the )ro)osed shelf=life statistical and regression analysis of the data have been provided to support the proposed shelf5life" 6f relevant the sta*ility of the )roduct after first o)ening> reconstitution or dilution 2as applicable4 has been investigated" $de,uate storage instructions and time=limits for use of the )roduct after first opening or reconstitution or dilution have been provided on the draft product label in any package insert and in the )ata ;heet"

!""

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

6ro.ided

NDA

F&$EI"&VA EN(E
10 (om)liance with Good (linical Research 6ractice -G(R6/ #he biostudy report includes 2a4 the dates for the trial and 2b/ the dates and times of dosage and 2c4 dates of analysis of the plasma0serum0urine samples and 2d4 details of the sites where the clinical and analytical aspects of the study were carried out" #he study report includes 2a4 names 2b4 affiliations and 2c4 signatures for each of the responsible investigators and analysts" #he study was carried out in accordance with the re,uirements of G(R6 and with ethics committee a))ro.al " $ copy of the study )rotocol has been provided" 'u*Ject ages> se1es> weights and heights 2and smoking habits if relevant4 have been provided" (linical and la*oratory screening data for the subHects are included in the study report" #he details of any ad.erse reactions 2if any4 eJperienced by the subHects during or after the study are included in the study report"

+0 Formulations com)ared and their I( data #he reference )roduct is clearly defined #he source from which the *atch of reference )roduct was obtained is clearly identified" 6f the *atch of reference )roduct was obtained from outside 7ew Eealand appropriate evidence that its formulation was definitely the same as that distributed in 7ew Eealand has been provided" #he batch number0code and source of *ul2 acti.e ingredient used to manufacture the *atch trial medicine-s/ are identified" #he *atch si@e of the trial medicine 2s4 was full production scale in the case of production scale being less than 100 000 solid dose units or at least 10M of full production scale or 100 000 units whichever is the greater unless Hustified in the case of production batch being more than 100 000 units" Complete ?uality control data 2incl" !ean assay content uniformity disintegration and dissolution4 have been provided for the batches of reference )roduct and trial medicine used in the biostudy" #he batches of reference and trial medicines used in the biostudy had not e1)ired at the time of the study" #he in vitro dissolution )rofiles of the medicines compared in vivo in the biostudy have been compared and shown to be comparable or any significant differences have been discussed and Hustified"

%22

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

6ro.ided

NDA

30 'tudy design #he study design is reported in detail" #he dose of medicine given is reported" $ny meals consumed during the study periods are defined 2e"g" menus provided4"" $ny restrictions on su*Jects4 diet> )hysical acti.ity> and use of other medication before and during the study are defined" 'am)ling times are clearly defined" $ny significant de)artures from the )rotocol are detailed and eJplained" #he time between the different phases of the study is defined" 6f the study was Psingle dose the washout period was ade,uate and plasma0serum levels of drug and metabolites were back to Lero for each subHect before the neJt dose was administered" 6f the study was Psteady stateQ evidence that a steady state was actually achieved in each phase of the study before blood sampling was commenced has been provided" 6f relevant any subHect dro)outs and withdrawals have been eJplained"

50 Assay method and )rocedures #he *ody fluids monitored are clearly defined" #he entities measured 2unchanged drug substance and0or active0significant metabolites4 are clearly defined" #he assay method sam)le )re)aration and assay )rocedures are described in detail" #he sources of the reference standards 2drug substance any metabolites and internal standards4 used in the analytical validation and assay procedures are reported"

%2!

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

6ro.ided

NDA

80 6re=study .alidation of assay )rocedure Validation data were generated at the site used for assaying the actual study samples" ')ecificity has been validated for each entity measured" Re)resentati.e chromatograms or other data have been submitted to confirm the specificity of the assays" #he minimum ?uantifia*le concentration -MI(/ has been validated :!OC is the concentration with ';) . ca 20M"< &ntra=assay )recision has been validated 2e"g" ';) typically R10M and 20M near !OC4" &nter=assay accuracy has been validated 2e"g" ';) typically R10M and 20M near !OC4" Accuracy 2e"g" standards within R10M of actual4 has been validated" inearity 2r10"%%4 2or the calibration curve4 has been established using + or more standards with appropriate concentrations across the range of concentrations encountered in the study" #he reco.ery has been measured at low medium and high concentrations and is reasonably uniform" #he sta*ility of the samples during storage and freeLe5thaw cycling has been established"

90 Iuality control of study sam)le assays $t least + daily cali*ration standards with concentrations covering the re,uired range were used in the assays of the study samples" #he in.estigators4 criteria for acce)ting or reJecting results have been provided" #he I( sam)le assay data have been reported"

:0 6harmaco2inetic )arameters #he individual su*Ject concentration .s0 time data have been reported in both tabular and graphical form" #he mean concentration .s0 time data have been reported in both tabular and graphical form" Only concentrations at or a*o.e the MI( have been used in calculation of elimination rates and $-Cs" 6f actual and nominal sam)ling times were significantly different the actual times were used in calculation of pharmacokinetic parameters"

;0 'tatistical analyses of results #he statistical analyses of the #maJ CmaJ 2and Cmin for a steady state study4 and $-C data are reported"

%2%

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

#he results ha.e *een normalised 2if necessary4 for mean potencies of the administered formulations"

(omments: ???????????????????????????????????? ???????????????????????????????????? ???????????????????????????????????? ???????????????????????????????????? ???????????????????????????????????? ???????????????????????????????????? ???????????????????????????????????? ???????????????????????????????????? ???????????????????????????????????? ???????????????????????????????????? ???????????????????????????????????? ???????????????????????????????????? ???????????????????????????????????? ???????????????????????????????????? ???????????????????????????????????? ???????????????????????????????????? ???????????????????????????????????? ???????????????????????????????????? ???????????????????????????????????? ???????????????????????????????????? ???????????????????????????????????? ???????????????????????????????????? ????????????????????????????????????

%2:

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

A))endi1 8:

(MN Form A

%24

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

(7ANGE! ME!&(&NE N$#&F&(A#&$N


F$RM A
#his form is to be used when notifying a material change 2including self5assessable changes4 to an approved #ype 6 product 2lower risk medicine4 or a #ype 66 product 2intermediate5 or higher5risk medicine other than a biological or biotechnological product 5 but including antibiotics and like substances derived from micro5organisms4" -se C!7 9orm A for a biological or biotechnological product 2i"e" vaccine serum allergen medicinal product derived from human blood or plasma or immunological medicinal product and any product derived from biotechnology4 )o not use this form for notifying a changed related product" -se the C'87 form instead"

'ection 1:

6roduct details

Copy details from the database report for the currently approved product" $ separate form must be used for each different product 2name / dose form / active ingredient2s4 / strength / classification / flavour as applicable4"

6roduct name: Medsafe File No: ##+05 !ose form: 'trength: (lassification : #y)e of )roduct:
(%ick one) #y)e & #y)e && ower=ris2 medicines &ntermediate=ris2 or 7igher=ris2 medicines other than *iological or *iotechnological )roducts -*ut including anti*iotics and li2e su*stances deri.ed from micro=organisms/

%29

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001
(MN Form A

'ection +: declaration

A))licant

and

')onsor

details

and

$n accordance with section 25 of the "edicines #ct 1?>1- $ here,y notify the *irector8 @eneral of Health of material changes proposed for this product0 $ certify that the information supplied is correct to the ,est of my knowledge and that no relevant information has ,een omitted0

Name> designation and address of )erson su*mitting the notification:


:$ll correspondence relating to the notification will be sent to this person unless otherwise re,uested"<

Email address:

'ignature: =============================== !ate: =================== ')onsor name and address:

%27

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001
(MN Form A

'ection 3:
&nstructions

6ro)osed changes

1" #ick the boJ2es4 in the left hand column beside the description2s4 that most accurately reflects the changes for which approval is sought" #he main change and the conse,uential changes listed under the F)escription of changeG are all covered by the fee shown in the F8roduct type S feeG column" Where no product type is specified in the F8roduct type and feeG column the same fee applies to all product types" 2" 6t is not necessary to submit pages listing change descriptions that are not relevant to the notification" K" 9or each boJ ticked write the appropriate fee in the F9ee to payG column" $dd together all amounts in the F9ee to payG column and transfer this total to the fee calculation boJ in ;ection +" (" When a self5assessable change is notified at the same time as other changes for which a fee is paid the T200 administrative fee for the self5assessable change does not apply 2eJcept in the case of a data sheet update where the update is independent and not conse,uential of any of the proposed changes4" F70$G 2not applicable4 should be written in the F9ee to payG column for the self5 assessable change" +" 6f applicable the Consumer !edicine 6nformation 2C!64 for the product should also be updated in line with the changes and a revised version forwarded to !edsafe once the consent letter for the C!7 or ;$C7 has been received" #here is no additional fee for the C!6"

6roduct name
Note: 6f a product is to be marketed under a new name in addition to the eJisting name it is a new product and a 7ew !edicine $pplication must be completed"

;ick ,o) 6roduct name

*escription of change

Product type . fee T(00 for each new name

'ee to pay %A&

new )roduct name to re)lace e1isting name no change in formulation Conse,uential changes included 2if applicable4 areD revised data sheet and labelling

%25

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001
(MN Form A

Formulation
Note: 6f a formulation change results in a change in the actual manufacturing process this must be separately notified as a F9inished product manufacturing processG change in the F9inished productG section of this form"

;ick ,o)

*escription of change Formulation = Grade 1 change in o.erage of an acti.e ingredient or e1ci)ient> or other e1ci)ient change where either: the )roduct is one for which com)arati.e *ioa.aila*ility data are not re?uiredO or the change is not considered li2ely to affect *ioa.aila*ility or sta*ility Conse,uential changes included 2if applicable4 areD new or revised specifications for eJcipient revised specifications for finished product revised labelling and data sheet amended batch manufacturing documentation provided there is no significant change in manufacturing process Formulation = Grade + changed acti.e ingredient salt> or change in status of ingredient from acti.e to e1ci)ient> or remo.al of acti.e ingredient with no other changes change not considered li2ely to affect sta*ility Conse,uential changes included 2if applicable4 areD new specifications0test methods for active ingredient and finished product revised labelling and data sheet amended batch manufacturing documentation provided there is no significant change in manufacturing process Formulation = Grade 3 changed acti.e ingredient salt or remo.al of acti.e ingredient with no other changes sta*ility study included Conse,uential changes included 2if applicable4 areD new specifications0test methods for active ingredient and finished product revised labelling and data sheet amended batch manufacturing documentation provided there is no significant change in manufacturing process

Product type . fee T&00 for any number of eJcipient changes

'ee to pay %A&

6D T&00 66D 7ot permitted 27!$ re,uired4

6D T1200 66D 7ot permitted 27!$ re,uired4

%26

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001
(MN Form A

Formulation -contPd/
;ick ,o) *escription of change Formulation = Grade 5 e1ci)ient change that may affect> or is considered li2ely to affect> *ioa.aila*ility> sta*ility or safety 2see ;ections ("N"1 and &"K of the Guidelines for details4 Conse,uential changes included 2if applicable4 areD new or revised specifications0test methods for eJcipient revised labelling and data sheet Product type . fee 6D T1200 66D T2(00 for any number of eJcipient changes 'ee to pay %A&

Acti.e ingredient
;ick ,o) *escription of change Acti.e ingredient manufacturing site new site of manufacture manufacturing )rocess unchanged Acti.e ingredient manufacturing )rocess = Grade 1 new manufacturing )rocess (ertificate of 'uita*ility )ro.ided in lieu of !MF Conse,uential changes included 2if applicable4 areD new site of manufacture Acti.e ingredient manufacturing )rocess = Grade + new manufacturing )rocess !MF or e?ui.alent documentation su))lied Conse,uential changes included 2if applicable4 areD process validation for active ingredient revised specifications0test methods for active ingredient new site of manufacture Product type . fee T(00 for any number of new sites 6D 7ot applicable 66D T(00 for any number of new sites 6D 7ot applicable 66D T1N00 for each new process 'ee to pay %A&

%2"

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001
(MN Form A

Acti.e ingredient -cont4d/


;ick ,o) *escription of change Acti.e ingredient s)ecificationsDtest methods = Grade 1 tightening of limits for acti.e su*stance Acti.e ingredient s)ecificationsDtest methods = Grade + new s)ecificationsDtest methods for a su*stance controlled according to a )harmaco)oeial monogra)h -resulting from change to a different )harmaco)oeia> not sim)ly u)dating to the latest edition/ Acti.e ingredient s)ecificationsDtest methods = Grade 3 ado)tion of additional or different s)ecificationsDtest methods not s)ecified in the )harmaco)oeial monogra)h for an acti.e ingredient otherwise controlled according to a )harmaco)oeial monogra)h Acti.e ingredient s)ecificationsDtest methods = Grade 5 re.ised s)ecificationsDtest methodsDtesting )rotocol for a su*stance not controlled according to a )harmaco)oeial monogra)h 6D T(00 66D T&00 for each active ingredient T(00 for each active T(00 Product type . fee T200 2self5assessable4 'ee to pay %A&

E1ci)ient
;ick ,o) *escription of change E1ci)ient s)ecificationsDtest methods = Grade 1 re.ised s)ecificationsDtest methods for a su*stance controlled according to a )harmaco)oeial monogra)h -resulting from change to a different )harmaco)oeia> not sim)ly u)dating to the latest edition/ E1ci)ient s)ecificationsDtest methods = Grade + re.ised s)ecificationsDtest methods for a su*stance not controlled according to a )harmaco)oeial monogra)h Product type . fee T200 2self5assessable4 for any number of eJcipients 'ee to pay %A&

T(00 for each eJcipient

%!2

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001
(MN Form A

E1ci)ient -cont4d/
;ick ,o) *escription of change E1ci)ient s)ecificationsDtest methods = Grade 3 ado)tion of additional or different s)ecificationsDtest methods not s)ecified in the )harmaco)oeial monogra)h for an e1ci)ient otherwise controlled according to a )harmaco)oeial monogra)h Product type . fee T(00 for each eJcipient 'ee to pay %A&

Finished )roduct
;ick ,o) *escription of change Finished )roduct )ac2ing site new )ac2ing site that is not a site of manufacture includes o.erla*elling Finished )roduct manufacturing site = Grade 1 no change in manufacturing )rocess or ty)e of e?ui)ment used s)ecificationsDtest methods unchanged Conse,uential changes included 2if applicable4 areD packing at same site Finished )roduct manufacturing site = Grade + change in manufacturing )rocess or ty)e of e?ui)ment used Conse,uential changes included 2if applicable4 areD packing at same site Finished )roduct manufacturing )rocess = Grade 1 ty)e of manufacturing )rocess unchanged> *ut changes to mi1ing times> *atch scaling> ty)e of e?ui)ment etc0 Conse,uential changes included 2if applicable4 areD revised specifications0test methods new site of manufacture and packing 6D T&00 66D T1200 for each new process 6D T1N00 66D T2000 Product type . fee T(00 for any number of sites 'ee to pay %A&

T(00 for each new site

%!!

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001
(MN Form A

Finished )roduct -cont4d/


;ick ,o) *escription of change Finished )roduct manufacturing )rocess = Grade + new ty)e of manufacturing )rocess Conse,uential changes included 2if applicable4 areD revision or reconfirmation of shelf life revised specifications0test methods new site of manufacture and packing Finished )roduct s)ecificationsDtest methods = Grade 1 re.ised s)ecificationsDtest methods no change in manufacturing )rocess )roduct controlled according to a )harmaco)oeial monogra)h -resulting from change to a different )harmaco)oeia> not sim)ly u)dating to the latest edition/ Finished )roduct s)ecificationsDtest methods = Grade + tightening of limits for acti.e su*stance no other changes to s)ecifications no changes to test methods Finished )roduct s)ecificationsDtest methods = Grade 3 ado)tion of additional or different s)ecificationsDtest methods not s)ecified in the )harmaco)oeial monogra)h for a )roduct otherwise controlled according to a )harmaco)oeial monogra)h Finished )roduct s)ecificationsDtest methods = Grade 5 re.ised s)ecificationsDtest methods no change in manufacturing )rocess )roduct not controlled according to a )harmaco)oeial monogra)h Finished )roduct s)ecificationsDtest methods = Grade 8 change in sha)e> engra.ing or coding of ta*lets no change in dissolution or *ioa.aila*ility T200 2self assessable4 6D T&00 66D T1200 T(00 T200 2self5assessable4 Product type . fee 6D T1N00 66D T2000 for each new process 'ee to pay %A&

T200 2self5assessable4

%!%

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001
(MN Form A

6roduct sta*ility and )ac2aging


;ick ,o) *escription of change 'helf lifeDstorage conditions = Grade 1 decrease in storage tem)erature from <3,( to <+8( with no change in shelf life and no other changes addition of a statement such as A6rotect from lightB Conse,uential changes included 2if applicable4 areD revised labelling and data sheet 'helf lifeDstorage conditions = Grade + re.ised shelf life andDor storage conditions with no other changes Conse,uential changes included 2if applicable4 areD revised labelling and data sheet (ontainerDclosureD)ac2aging = Grade 1 new )ac2 si@e e.idence )ro.ided that sta*ility study not re?uired no effect on dose measurement or dose deli.ery Conse,uential changes included 2if applicable4 areD revised labelling and data sheet revised packaging specifications (ontainerDclosureD)ac2aging = Grade + new container or closure ty)e andDor new )ac2 si@e andDor new )ac2aging material ty)e e.idence )ro.ided that sta*ility study not re?uired no effect on dose measurement or dose deli.ery Conse,uential changes included 2if applicable4 areD revised labelling and data sheet revised packaging specifications (ontainerDclosureD)ac2aging = Grade 3 new container or closure ty)e andDor new )ac2 si@e andDor new )ac2aging material ty)e e.idence )ro.ided that sta*ility study not re?uired affects dose measurement or dose deli.ery Conse,uential changes included 2if applicable4 areD revised labelling and data sheet revised packaging specifications T&00 for each new container0closure0 packaging combination T(00 for any number of new container0 closure0packaging combinations T200 2self5assessable4 T&00 Product type . fee T200 2self5assessable4 'ee to pay %A&

%!:

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001
(MN Form A

6roduct sta*ility and )ac2aging -cont4d/


;ick ,o) *escription of change (ontainerDclosureD)ac2aging = Grade 5 new container or closure ty)e andDor new )ac2 si@e andDor new )ac2aging material ty)e re.ised shelf life andDor storage conditions -sta*ility study included/ does not affect dose measurement or dose deli.ery Conse,uential changes included 2if applicable4 areD revised labelling and data sheet revised packaging specifications (ontainerDclosureD)ac2aging = Grade 8 new container or closure ty)e andDor new )ac2 si@e andDor new )ac2aging material ty)e re.ised shelf life andDor storage conditions -sta*ility study included/ affects dose measurement or dose deli.ery Conse,uential changes included 2if applicable4 areD revised labelling and data sheet revised packaging specifications T1N00 for each container0 closure0 packaging combination Product type . fee T1200 for each new container0closure0 packaging combination 'ee to pay %A&

&ndications and dosage


;ick ,o) *escription of change &ndicationsDdosage = Grade 1 new indication -see section 30101 of the Guidelines for details/ su))orting clinical data re?uired Conse,uential changes included 2if applicable4 areD new dosage instructions revised data sheet and labelling
Note: C!7 will generally be referred under section 2(2+4"

Product type . fee T1N00 for each new indication

'ee to pay %A&

&ndicationsDdosage = Grade + modified indication -see section 30101 of the Guidelines for details/ su))orting clinical data re?uired Conse,uential changes included 2if applicable4 areD new dosage instructions revised data sheet and labelling
Note: C!7 will generally be referred under section 2(2+4"

T&00 for each modified indication

%!4

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001
(MN Form A

&ndications and dosage -cont4d/


;ick ,o) *escription of change &ndicationsDdosage = Grade 3 new dosage regimen no change to indications su))orting clinical data re?uired Conse,uential changes included 2if applicable4 areD new dosage instructions revised data sheet and labelling &ndicationsDdosage = Grade 5 re.ised wording of indicationsDdosage with no actual change to indications or dosage Conse,uential changes included 2if applicable4 areD revised data sheet and labelling &ndicationsDdosage = Grade 8 new or re.ised indicationsDdosage for a multi= source medicine to match indications a))ro.ed for inno.ator )roduct Conse,uential changes included 2if applicable4 areD revised data sheet and labelling (ontraindications> Warnings and 6recautions rela1ation of contraindications> andDor rela1ation of warnings and )recautions regarding use in )regnancy> lactation or )articular )o)ulationD)atient su*grou)s su))orting clinical data re?uired Conse,uential changes included 2if applicable4 areD revised data sheet and labelling T&00 T(00 T(00 Product type . fee T&00 for each new dosage regimen

'ee to pay %A&

!ata sheet
;ick ,o) *escription of change !ata sheet = miscellaneous changes u)date or addition to safety information with no change to a))ro.ed )roduct details> andDor e1)ansion of )harmaco2inetic andDor )harmacodynamic data> andDor change in name or address of distri*utor with no change to a))ro.ed )roduct details Product type . fee T200 per data sheet 2self5assessable4 'ee to pay %A&

%!9

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001
(MN Form A

a*elling
;ick ,o) *escription of change a*elling = Grade 1 re=design of la*el> andDor change in name and address of distri*utor no change to )roduct name> strength> dose form> dosage instructions or indications Product type . fee T200 2self5assessable4 7ot applicable if a change of the classification makes the product a Controlled )rug T(00 'ee to pay %A&

a*elling = Grade + design or re=design of a New Zealand com)liant la*el andDor change in the classification to (ontrolled !rug no change in actual strength> *ut a change in the way the strength is e1)ressed -if a))lica*le/ a*elling = Grade 3 re?uest for a la*elling e1em)tion> or re?uest for renewal of a la*elling e1em)tion N$# A66 &(AF E for a ($N#R$ E! !R"G

T(00 2plus T200 for each additional name0 dose form0 strength0 flavour4

$ther
;ick ,o) ')onsor change of )roduct s)onsor from one com)any to another -not sim)ly a change in the name or address of an e1isting s)onsor/ Conse,uential changes included 2if applicable4 areD change of name and address of distributor on label and in data sheet" &nterchangea*le Multi=source Medicines -&MM/ ist a))lication for inclusion of a )roduct on the &MM list su))orting *ioe?ui.alence data re?uired *escription of change Product type . fee T200 2self5assessable4 Note: $ C!70C'87 for change in packing site2s4 may also be re,uired" 'ee to pay %A&

6D 7ot applicable 66D T2(00

%!7

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001
(MN Form A

'ection 5:

'ummary of )ro)osed changes


"se a se)arate summary sheet for each change0

!escri)tion of change -co)y heading from A!escri)tion of changeB *o1 in 'ection 3/:

'ummary of current and )ro)osed details: (urrent )roduct details 6ro)osed details

Reason for change:

(onse?uential changes:

Acce)tance o.erseas:

%!5

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001
(MN Form A

'ection 8:

Fee details

Complete this section once for each notification package submitted" 6f you are simultaneously notifying an identical change or set of changes to a number of products list all the products covered by the notification in the following table" @ach dose form and each strength and flavour of each dose form of a product must be separately listed" Note: $ separate copy of ;ections 1 and 2 of this notification form must be completed for each of the products listed" Only one copy of ;ections K and ( is re,uired" $ll the forms must be submitted in the same notification package"

File No0

6roduct name

!ose form

'trength

Fee calculation
Note 1: 6f you are notifying identical changes to a number of products the evaluation fee shown in the boJ below must be the largest fee that would apply to any single product" 9or eJample if the notification covers #ype 6 and #ype 66 products the evaluation fee applicable for a #ype 66 product must be entered below" Note +: 6n no case will the C!70C'87 evaluation fee for a single product eJceed T* &00 for a medicine or T+ +00 for a related product" Note 3: $dditional names dose forms strengths and flavours are each regarded as Fadditional productsG and each one attracts an additional T200 2administrative4 fee" Note 5: #he fee for a changed data sheet is T200 )er data sheet

E.aluation fee calculated for a single )roduct:


:#otal all amounts in F9ee to payG boJes in ;ection K<

0,,

Administrati.e fee for ===== additional )roducts Q M+,, each #otal fee:

M 0,, ============= M 0,,

Method of )ayment:

Che,ue enclosed

)irect credit 2details enclosed4

Check and indicate that the notification package sent to !edsafe contains the following 2as applicable4D

(+ or N,A)

$ completed copy of ;ections 1 and 2 of the C!70C'87 form for each product covered by the notification One completed copy of ;ections K ( and + of the C!70C'87 form One copy of the supporting data $ copy of the current product database report2s4 $ copy of the label and a completed checklist and declaration if the notification includes a self5assessed labelling or data sheet change $ copy of an assessment report from an appropriate overseas regulatory authority
(End o or#)

%!6

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

A))endi1 9:

(MN Form F

%!"

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

(7ANGE! ME!&(&NE N$#&F&(A#&$N


F$RM F
#his form is to be used when notifying a material change 2including self5assessable changes4 to an approved #y)e &&& -*iological or *iotechnological/ product 2i"e" a vaccine recombinant product monoclonal antibody or variant thereof or a medicinal product derived from blood or plasma4" -se C!7 9orm $ for any other 2#ype 60664 medicine including antibiotics and like substances derived from micro5organisms" )o not use this form for notifying a changed related product"

'ection 1: 6roduct details


Copy details from the database report for the currently approved product" $ separate form must be used for each different product 2name / dose form / active ingredient / strength / classification as applicable4"

6roduct name: File No: ##+05 !ose form: 'trengthD6otency: (lassification:

'ection +: A))licant and ')onsor details and declaration


$n accordance with section 25 of the "edicines #ct 1?>1- $ here,y notify the *irector8@eneral of Health of material changes proposed for this product0 $ certify that the information supplied is correct to the ,est of my knowledge and that no relevant information has ,een omitted0 Name> designation and address of )erson su*mitting the notification:
:$ll correspondence relating to the notification will be sent to this person unless otherwise re,uested"<

Email address:

'ignature: ========================= !ate: ================ ')onsor name and address:

%%2

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001
(MN Form F

'ection 3: 6ro)osed changes


&nstructions 1" #ick the boJ2es4 in the left hand column beside the description2s4 that most accurately reflects the changes for which approval is sought" #he main change and the conse,uential changes listed under the F)escription of changeG are all covered by the fee shown in the F8roduct type S feeG column" Where no product type is specified in the F8roduct type and feeG column the same fee applies to all product types" 2" 6t is not necessary to submit pages listing change descriptions that are not relevant to the notification" K" 9or each boJ ticked write the appropriate fee in the F9ee to payG column" $dd together all amounts in the F9ee to payG column and transfer this total to the fee calculation boJ in ;ection +" (" When a self5assessable change is notified at the same time as other changes for which a fee is paid the T200 administrative fee for the self5assessable change does not apply 2eJcept in the case of a data sheet update where the update is independent and not conse,uential of any of the proposed changes4" F70$G 2not applicable4 should be written in the F9ee to payG column for the self5assessable change"

6roduct name
Note: 6f a product is to be marketed under a new name in addition to the eJisting name it is a new product and a 7ew !edicine $pplication must be completed"

;ick ,o)

*escription of change 6roduct name new )roduct name to re)lace e1isting name no change in formulation Conse,uential changes included 2if applicable4 areD revised data sheet and labelling

Product type . fee T(00 for each new name

'ee to pay %A&

FormulationDE1ci)ients
Note: 6f a formulation change is associated with a change in the actual bulk active manufacturing process this must be separately notified as a FAulk $ctive manufacturing processG change in the FAulk $ctiveG section of this form

;ick ,o)

*escription of change Formulation = Grade 1 change of e1ci)ients including the addition or remo.al of e1ci)ients Conse,uential changes included 2if applicable4 areD new or revised specifications for eJcipient revised data sheet and labelling amended batch manufacturing documentation provided there is no significant change in manufacturing process Formulation R Grade + strain u)date of acti.e ingredient for influen@a .accines

Product type . fee T1N00 for any number of eJcipient changes

'ee to pay %A&

T(00 for any number of strains

%%!

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001
(MN Form F

Ful2 Acti.e
;ick ,o) *escription of change Ful2 Acti.e manufacturing site (hange in site of manufacture of any stage in the )rocess u) to> and including> the manufacture of the final *ul20 #his would *e considered as a New Medicine A))lication Conse,uential change 2if applicable4 !ethod of manufacture Ful2 Acti.e methods of manufacture (hange in any ste) of the method of manufacture0 #his would include> *ut is not restricted to: changes in mi1ing time> *atch scaling ty)e of e?ui)ment new master cell *an2 new wor2ing cell *an2 new source-s/ of )lasma for *lood )roducts (hange in site of lyo)hilisation Re.alidation of lyo)hilisation )rocess Acti.e ingredient method of manufacture T(00 No change to the actual manufacturing )rocess or ty)e of e?ui)ment used ')ecificationsDtest methods unchanged Editorial changes for the manufacturing )rocess records only T1N00 per step change to a maJimum of T*&00 #his category of change could be eJpected to be referred as an 7!$ under section 2(2+4 Product type . fee T*&00 'ee to pay %A&

T1N00 T1N00

%%%

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001
(MN Form F

Finished )roduct manufacture and )ac2ing


;ick ,o) *escription of change Finished )roduct manufacturing site new site for dis)ensing final *ul2 finished )roduct into )rimary containers Finished )roduct secondary )ac2ing site new secondary )ac2ing site that is not a site of manufacture )ac2ing finished )roduct into cartons includes o.erla*elling Finished )roduct manufacturing )rocess = Grade 1 ty)e of manufacturing )rocess unchanged> *ut changes to mi1ing time> *atch scaling> ty)e of e?ui)ment etc0 Conse,uential changes included 2if applicable4 areD new site of manufacture and packing Finished )roduct manufacturing )rocess R Grade + new ty)e of manufacturing )rocess Conse,uential changes included 2if applicable4 areD revision or reconfirmation of shelf life new site of manufacture and packing Finished )roduct manufacturing )rocess T(00 No change to the actual manufacturing )rocess or ty)e of e?ui)ment used ')ecificationsDtest methods unchanged Editorial changes for the manufacturing )rocess records only T1N00 Product type . fee T1N00 for each new site 'ee to pay %A&

T(00 for any number of sites

T1N00

%%:

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001
(MN Form F

#est methods and s)ecifications


;ick ,o) *escription of change #est methods and s)ecifications = Grade 1 change to any method used to assay )otency of each acti.e moiety #est methods and s)ecifications = Grade + change to s)ecifications used to descri*e )otency #est methods and s)ecifications = Grade 3 change to standard used in assessment of )otency #est methods and s)ecifications = Grade 5 change to any method used to assess other )hysical or chemical )ro)erties of the )roduct #est methods and s)ecifications = Grade 8 addition D remo.al D change to any s)ecification used to descri*e other )hysical or chemical )ro)erties #est methods and s)ecifications = Grade 9 tightening of s)ecification limits for acti.e ingredient T200 2self assessable4 for any number of active ingredients T&00 T&00 T1N00 for each active moiety potency specification T1N00 Product type . fee T1N00 'ee to pay %A&

%%4

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001
(MN Form F

6roduct sta*ility and )ac2aging


;ick ,o) *escription of change 'helf lifeDstorage conditions = Ful2 Acti.es and &ntermediate Ful2s re.ised shelf=life andDor storage conditions with no other changes 'helf lifeDstorage conditions = Finished 6roduct re.ised shelf life andDor storage conditions with no other changes Conse,uential changes included 2if applicable4 areD revised labelling and data sheet (ontainerDclosureD)ac2aging = Grade 1 new container or closure andDor new )ac2 si@e andDor new )ac2aging material ty)e re.ised shelf=life andDor storage conditions su))orting sta*ility data )ro.ided no effect on dose measurement or dose deli.ery Conse,uential changes included 2if applicable4 areD revised packaging specifications revised labelling and data sheet (ontainerDclosureD)ac2aging = Grade + new container or closure andDor new )ac2 si@e andDor new )ac2aging material ty)e re.ised shelf=life andDor storage conditions su))orting sta*ility data )ro.ided changes affect dose measurement or dose deli.ery Conse,uential changes included 2if applicable4 areD revised packaging specifications revised labelling and data sheet (ontainerDclosureD)ac2aging = Grade 3 new )ac2 si@e e.idence )ro.ided that no sta*ility data re?uired no effect on dose measurement or dose deli.ery Conse,uential changes included 2if applicable4 areD revised labelling and data sheet revised packaging specifications T200 2self assessable4 T1N00 for each container0closure packaging combination T&00 Product type . fee T&00 for each bulk active or each process intermediate T&00

'ee to pay %A&

%%9

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001
(MN Form F

(hanges affecting the !iluent com)onent of #y)e &&& -*iological or *iotechnological/ )roducts0
&f the diluent contains *iologicalD*lood )roduct ingredient> use (MN Form F and select a))ro)riate category of change0 &f the diluent !$E' N$# contain *iologicalD*lood )roduct ingredient> use (MN Form A and select a))ro)riate category of change0

&ndications and dosage


;ick ,o) *escription of change &ndicationsDdosage = Grade 1 new indication -see 'ection 30101 of the Guidelines for details/ su))orting clinical data re?uired Conse,uential changes included 2if applicable4 areD new dosage instructions revised data sheet and labelling Note: C!7 will generally be referred under section 2(2+4 &ndicationsDdosage = Grade + modified indication -see 'ection 30101 of the Guidelines for details/ su))orting clinical data re?uired Conse,uential changes included 2if applicable4 areD new dosage instructions revised data sheet and labelling Note: C!7 will generally be referred under section 2(2+4 &ndicationsDdosage = Grade 3 new dosage regimen no change to indications su))orting clinical data re?uired Conse,uential changes included 2if applicable4 areD new dosage instructions revised data sheet and labelling T&00 for each new dosage regimen T&00 for each modified indication Product type . fee T1N00 for each new indication 'ee to pay %A&

%%7

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001
(MN Form F

&ndications and dosage -cont4d/


;ick ,o) *escription of change &ndicationsDdosage = Grade 5 re.ised wording of indicationsDdosage with no actual change to indications or dosage Conse,uential changes included 2if applicable4 areD revised data sheet and labelling &ndicationsDdosage = Grade 8 new or re.ised indicationsDdosage for a multi= source medicine to match indications a))ro.ed for inno.ator )roduct Conse,uential changes included 2if applicable4 areD revised data sheet and labelling (ontraindications> Warnings and 6recautions rela1ation of contraindications> andDor rela1ation of warnings and )recautions regarding use in )regnancy> lactation or )articular )o)ulationD)atient su*grou)s su))orting clinical data re?uired Conse,uential changes included 2if applicable4 areD revised data sheet and labelling T&00 T(00 Product type . fee T(00 'ee to pay %A&

a*elling
;ick ,o) *escription of change a*elling = Grade 1 a*elling for this category must *e *ased on> and su*mitted with> currently a))ro.ed la*elling0 re=design of la*el> andDor change in name and address of distri*utor no change to )roduct name> strength> dose form> dosage instructions or indications> or change in dosage to Aas directed *y a )hysicianB Product type . fee T200 2self5assessable4 'ee to pay %A&

%%5

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001
(MN Form F

a*elling -cont4d/
;ick ,o) *escription of change a*elling = Grade + design or re=design of a New Zealand com)liant la*el no change in actual strength> *ut a change in the way the strength is e1)ressed -if a))lica*le/ any la*elling change not co.ered *y a*elling R Grade 1 or a*elling R Grade 3 a*elling = Grade 3 re?uest for a la*elling e1em)tion> or re?uest for renewal of a la*elling e1em)tion T(00 2plus T200 for each additional name0 dose form0strength0 flavour4 Product type . fee T(00 'ee to pay %A&

!ata 'heet
;ick ,o) *escription of change !ata sheet = miscellaneous changes u)date or addition to safety information with no change to a))ro.ed )roduct details> andDor e1)ansion of )harmaco2inetic andDor )harmacodynamic data> andDor change in name or address of distri*utor with no change to a))ro.ed )roduct details Product type . fee T200 per data sheet" 2self5assessable4 'ee to pay %A&

$ther
;ick ,o) ')onsor change of )roduct s)onsor from one com)any to another -not sim)ly a change in the name or address of an e1isting s)onsor/ Conse,uential changes included 2if applicable4 areD change of name and address of distributor on label and in data sheet" Note: $ C!7 for change in packing site2s4 may also be re,uired" *escription of change Product type . fee T200 2self5assessable4 'ee to pay %A&

%%6

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001
(MN Form F

'ection 5:

'ummary of )ro)osed changes


"se a se)arate summary sheet for each change0

!escri)tion of change -co)y heading from A!escri)tion of changeB *o1 in 'ection 3/:

'ummary of current and )ro)osed details: (urrent )roduct details 6ro)osed details

Reason for change:

(onse?uential changes:

Acce)tance o.erseas:

%%"

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001
(MN Form F

'ection 8: Fee details


Complete this section once for each notification package submitted" 6f you are simultaneously notifying an identical change or set of changes to a number of products list all the products covered by the notification in the following table" @ach dose form and each strength and flavour of each dose form of a product must be separately listed" Note: $ separate copy of ;ections 1 and 2 of this notification form must be completed for each of the products listed" Only one copy of ;ections K and ( is re,uired" $ll the forms must be submitted in the same notification package"

File No0

6roduct name

!ose form

'trength

Fee calculation
Note 1: 6f you are notifying identical changes to a number of products the evaluation fee shown in the boJ below must be the largest fee that would apply to any single product" 9or eJample if the notification covers #ype 6 and #ype 66 products the evaluation fee applicable for a #ype 66 product must be entered below" Note +: 6n no case will the C!70C'87 evaluation fee for a single product eJceed T* &00 for a medicine or T+ +00 for a related product" Note 3: $dditional names dose forms strengths and flavours are each regarded as Fadditional productsG and each one attracts an additional T200 2administrative4 fee" Note 5: #he fee for a changed data sheet is T200 )er data sheet

E.aluation fee calculated for a single )roduct:


:#otal all amounts in F9ee to payG boJes in ;ection K<

0,,

Administrati.e fee for ===== additional )roducts Q M+,, each #otal fee:

M 0,, ============= M 0,,

Method of )ayment:

Che,ue enclosed

)irect credit 2details enclosed4

Check and indicate that the notification package sent to !edsafe contains the following 2as applicable4D

(+ or N,A)

$ completed copy of ;ections 1 and 2 of the C!70C'87 form for each product covered by the notification One completed copy of ;ections K ( and + of the C!70C'87 form One copy of the supporting data $ copy of the current product database report2s4 $ copy of the label and a completed checklist and declaration if the notification includes a self5assessed labelling or data sheet change $ copy of an assessment report from an appropriate overseas regulatory authority
(End o or#)

%:2

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

A))endi1 ::

(R6N Form

%:!

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

(7ANGE! RE A#E! 6R$!"(# N$#&F&(A#&$N


#his form is to be used when notifying a material change 2including self5assessable changes4 to an approved related product" )o not use this form for notifying a changed medicine" -se the appropriate C!7 9orm instead"

'ection 1:

6roduct details

Copy details from the database report for the currently approved product" $ separate form must be used for each different product 2name / dose form / strength / classification / flavour as applicable4"

6roduct name: #y)e of )roduct: 'trength: Medsafe File No: ##+05

'ection +: declaration

A))licant

and

')onsor

details

and

$n accordance with section 25 of the "edicines #ct 1?>1- $ here,y notify the *irector8 @eneral of Health of material changes proposed for this product0 $ certify that the information supplied is correct to the ,est of my knowledge and that no relevant information has ,een omitted0

Name> designation and address of )erson su*mitting the notification:


:$ll correspondence relating to the notification will be sent to this person unless otherwise re,uested"<

Email address:

'ignature: =============================== !ate: =================== ')onsor name and address:

%:%

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001
(R6N Form

'ection 3:

6ro)osed changes

&nstructions 1" #ick the boJ2es4 in the left hand column beside the description2s4 that most accurately reflects the changes for which approval is sought" #he main change and the conse,uential changes listed under the F)escription of changeG are all covered by the fee shown in the FfeeG column" 6t is not necessary to submit pages listing change descriptions that are not relevant to the notification" 2" 9or each boJ ticked write the appropriate fee in the F9ee to payG column" $dd together all amounts in the F9ee to payG column and transfer this total to the fee calculation boJ in ;ection +" K" When a self5assessable change is notified at the same time as other changes for which a fee is paid the T200 administrative fee for the self5assessable change does not apply" F70$G 2not applicable4 should be written in the F9ee to payG column for the self5 assessable change"

6roduct name
Note: 6f a product is to be marketed under a new name in addition to the eJisting name it is a new product and a 7ew !edicine $pplication must be completed"

;ick ,o) 6roduct name

*escription of change T(00

'ee

'ee to pay %A&

new )roduct name to re)lace e1isting name no change in formulation Conse,uential changes included 2if applicable4 areD revised labelling

for each new name

Formulation
Note: 6f a formulation change results in a change in the actual manufacturing process this must be separately notified as a F9inished product manufacturing processG change in the F9inished productG section of this form"

;ick ,o)

*escription of change Formulation = Grade 1 change in o.erage of an acti.e ingredient or e1ci)ient> or other e1ci)ient change the change is not considered li2ely to affect sta*ility Conse,uential changes included 2if applicable4 areD new or revised specifications for eJcipient revised specifications for finished product revised labelling T&00

'ee

'ee to pay %A&

for any number of eJcipient changes

%::

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001
(R6N Form

Formulation -cont4d/
Note: 6f a formulation change results in a change in the actual manufacturing process this must be separately notified as a F9inished product manufacturing processG change in the F9inished productG section of this form"

;ick ,o)

*escription of change Formulation = Grade + changed acti.e ingredient salt> or change in status of ingredient from acti.e to e1ci)ient> or remo.al of acti.e ingredient with no other changes change not considered li2ely to affect sta*ility Conse,uential changes included 2if applicable4 areD new specifications0test methods for active ingredient and finished product revised labelling Formulation = Grade 3 changed acti.e ingredient salt> or remo.al of acti.e ingredient with no other changes sta*ility study included Conse,uential changes included 2if applicable4 areD new specifications0test methods for active ingredient and finished product revised labelling T1200 T&00

'ee

'ee to pay %A&

Acti.e ingredient
;ick ,o) *escription of change Acti.e ingredient s)ecificationsDtest methods = Grade 1 tightening of limits for acti.e su*stance Acti.e ingredient s)ecificationsDtest methods = Grade + new or re.ised s)ecificationsDtest methods T(00 for each active 'ee T200 2self5assessable4 'ee to pay %A&

%:4

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001
(R6N Form

Finished )roduct
;ick ,o) *escription of change Finished )roduct )ac2ing site new )ac2ing site that is not a site of manufacture includes o.erla*elling> if re?uired Finished )roduct manufacturing site = Grade 1 no change in manufacturing )rocess or ty)e of e?ui)ment used s)ecificationsDtest methods unchanged )ac2ing at same site Finished )roduct manufacturing site = Grade + change in manufacturing )rocess or ty)e of e?ui)ment used )ac2ing at same site Finished )roduct manufacturing )rocess = Grade 1 ty)e of manufacturing )rocess unchanged> *ut changes to mi1ing times> *atch scaling> ty)e of e?ui)ment etc0 Conse,uential changes included 2if applicable4 areD revised specifications0test methods new site of manufacture and packing Finished )roduct manufacturing )rocess = Grade + new ty)e of manufacturing )rocess Conse,uential changes included 2if applicable4 areD revision or reconfirmation of shelf life revised specifications0test methods new site of manufacture and packing Finished )roduct s)ecificationsDtest methods re.ised s)ecificationsDtest methods no change in manufacturing )rocess T(00 T1N00 for each new process T&00 for each new process T(00 for any number of sites 'ee 'ee to pay %A&

T(00 for each new site

T1N00

%:9

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001
(R6N Form

6roduct sta*ility and )ac2aging


;ick ,o) *escription of change 'helf lifeDstorage conditions = Grade 1 decrease in storage tem)erature from <3,( to <+8( with no change in shelf life and no other changes addition of a statement such as A6rotect from lightB Conse,uential changes included 2if applicable4 areD revised labelling 'helf lifeDstorage conditions = Grade + re.ised shelf life andDor storage conditions with no other changes Conse,uential changes included 2if applicable4 areD revised labelling (ontainerDclosureD)ac2aging = Grade 1 new )ac2 si@e e.idence )ro.ided that sta*ility study not re?uired Conse,uential changes included 2if applicable4 areD revised labelling (ontainerDclosureD)ac2aging = Grade + new container or closure ty)e andDor new )ac2 si@e andDor new )ac2aging material ty)e e.idence )ro.ided that sta*ility study not re?uired Conse,uential changes included 2if applicable4 areD revised labelling (ontainerDclosureD)ac2aging = Grade 3 new container or closure ty)e andDor new )ac2 si@e andDor new )ac2aging material ty)e re.ised shelf life andDor storage conditions -sta*ility study included/ Conse,uential changes included 2if applicable4 areD revised labelling T1200 for each new container0closure0 packaging combination T(00 for any number of new container0 closure0packaging combinations T200 2self5assessable4 T&00 'ee T200 2self5assessable4 'ee to pay %A&

%:7

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001
(R6N Form

&ndications and dosage


;ick ,o) *escription of change &ndicationsDdosage = Grade 1 new indication -see section 30101 of the Guidelines for details/ Conse,uential changes included 2if applicable4 areD new dosage instructions revised labelling
Note: C!7 will generally be referred under section 2(2+4"

Product type . fee T1N00 for each new indication

'ee to pay %A&

&ndicationsDdosage = Grade + modified indication -see section 30101 of the Guidelines for details/ Conse,uential changes included 2if applicable4 areD new dosage instructions revised labelling
Note: C!7 will generally be referred under section 2(2+4"

T&00 for each modified indication

&ndicationsDdosage = Grade 3 new dosage regimen no change to indications Conse,uential changes included 2if applicable4 areD new dosage instructions revised labelling &ndicationsDdosage = Grade 5 re.ised wording of indicationsDdosage with no actual change to indications or dosage Conse,uential changes included 2if applicable4 areD revised labelling

T&00 for each new dosage regimen

T(00

%:5

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001
(R6N Form

a*elling
;ick ,o) *escription of change a*elling = Grade 1 re=design of la*el> andDor change in name and address of distri*utor no change to )roduct name> strength> dose form> dosage instructions or indications a*elling = Grade + design or re=design of a New Zealand com)liant la*el andDor change in the classification to (ontrolled !rug no change in actual strength> *ut a change in the way the strength is e1)ressed -if a))lica*le/ T(00 Product type . fee T200 2self5assessable4 'ee to pay %A&

$ther
;ick ,o) ')onsor change of )roduct s)onsor from one com)any to another -not sim)ly a change in the name or address of an e1isting s)onsor/ Conse,uential changes included 2if applicable4 areD change of name and address of distributor on label" *escription of change 'ee T200 2self5assessable4 Note: $ C'87 for change in packing site2s4 may also be re,uired" 'ee to pay %A&

%:6

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001
(R6N Form

'ection 5:

'ummary of )ro)osed changes


"se a se)arate summary sheet for each change0

!escri)tion of change -co)y heading from A!escri)tion of changeB *o1 in 'ection 3/:

'ummary of current and )ro)osed details: (urrent )roduct details 6ro)osed details

Reason for change:

(onse?uential changes:

%:"

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001
(R6N Form

'ection 8:

Fee details

Complete this section once for each notification package submitted" 6f you are simultaneously notifying an identical change or set of changes to a number of products list all the products covered by the notification in the following table" @ach dose form and each strength and flavour of each dose form of a product must be separately listed" Note: $ separate copy of ;ections 1 and 2 of this notification form must be completed for each of the products listed" Only one copy of ;ections K and ( is re,uired" $ll the forms must be submitted in the same notification package"

File No0
##+05 ##+05 ##+05 ##+05

6roduct name

'trength

Fee calculation
Note 1: 6f you are notifying identical changes to a number of products the evaluation fee shown in the boJ below must be the largest fee that would apply to any single product" 9or eJample if the notification covers #ype 6 and #ype 66 products the evaluation fee applicable for a #ype 66 product must be entered below" Note +: 6n no case will the C'87 evaluation fee for a single related product eJceed T+ +00" Note 3: $dditional names types strengths and flavours are each regarded as Fadditional productsG and each one attracts an additional T200 2administrative4 fee"

E.aluation fee calculated for a single )roduct:


:#otal all amounts in F9ee to payG boJes in ;ection K<

0,,

Administrati.e fee for ===== additional )roducts Q M+,, each #otal fee:

M 0,, ============= M 0,,

Method of )ayment:

Che,ue enclosed

)irect credit 2details enclosed4

Check and indicate that the notification package sent to !edsafe contains the following 2as applicable4D

(+ or N,A)

$ completed copy of ;ections 1 and 2 of the C!70C'87 form for each product covered by the notification One completed copy of ;ections K ( and + of the C!70C'87 form One copy of the supporting data $ copy of the current product database report2s4 $ copy of the label and a completed checklist and declaration if the notification includes a self5assessed labelling or data sheet change
(End o or#)

%42

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

A))endi1 ;:

a*elling !eclaration

%4!

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

AFE

&NG !E( ARA#&$N

Complete one declaration to cover all primary secondary and tertiary labels relating to each separate product 2name / dose form / strength / classification / flavour as applicable4

& declare that the la*el-s/ for """"""""""""""""""""""""""""""""""""""""""""""""""""""""""???????""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""


28roduct name dose form strength classification and flavour as applicable4

KMedsafe file No0 ##8,= """""""?"""""""""" L hasDha.e *een assessed and isDare in com)liance with the re?uirements of the legislation0 All information on the la*el-s/ is consistent with the details of the medicine currently a))ro.ed in New Zealand or descri*ed in the current New Medicine or Related 6roduct A))lication0 #he following documents are attached:
(tick) a*elling (hec2list-s/ (o)y of )re.iously a))ro.ed la*el-s/ (o)y or la*el-s/ colour draft of )ro)osed

'ignature: """"""""""""""""""""""""""""""""""""""""""""""""""" !ate"""""""""""""""""""""""""""" Name> designation and address of )erson su*mitting la*el:
:Note: $ll correspondence relating to the label will be sent to this person unless re,uested otherwise"<

Name and address of s)onsor:

%4%

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

A))endi1 <:

a*elling (hec2list for Medicines

%4:

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

AFE

2-se this checklist for all medicines including Controlled )rugs but not including contact lens solutions for which there is a separate checklist4

&NG (7E(H &'# F$R ME!&(&NE'

6roduct: """"""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""
27ame dose form and strength and flavour if applicable4

(lassification: """"""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""
28rescription 'estricted08harmacist Only 8harmacy Only General ;ales4

a*el assessed: """""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""


28rimary label on container ;econdary label on outer package4

(tick &ox)

10 6hysical a*el 2!edicines 'egs 1*4


6s the labelD a4 printed on or firmly and securely attached to the containerU b4 unlikely to become detached or defaced or illegible during useU c4 positioned so that it will not be damaged or removed when the container is openedU d4 not obscured by any other label or leaflet or any part of the product or packagingU

%es

+0 anguage and #e1t


a4 in @nglishU

2!edicines 'egs 1* and 1&4

6s all the information re,uired to be on the label

b4 in lettering that is clear distinct and legible and the height of letters with ascenders is not less than 0"*+mm in the case of a small label or not less than 1"+mm in any other caseU

30 6rinci)al !is)lay 6anel 2!edicines 'egs

1K S 1+ S $mendments4

)oes the label have a 8rincipal )isplay 8anel 28)84 that is visible when the container is stored in the normal mannerU )oes the 8)8 contain the following informationD a4 the trade name of the productU b4 the pharmacopoeial name0appropriate designation of the product or the name of each active ingredient and strengthU c4 the contents of the container 2weight volume or number4U d4 the dose form or presentationU

%44

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001
a*elling (hec2list for Medicines -cont4d/

(tick &ox)

50 $ther Re?uirements
2!edicines 'egs 1K 1N 1% 20 S $mendments4

%es No NDA

$" 6f the product contains a scheduled medicine does the label state in a prominent way the appropriate classification using one of the eJpressions belowU
-.rescription !edicineV or .rescription Only !edicineV or the acronym .O! or the symbol Rx Restricted !edicine or .(ar#acist Only !edicine or .(ar#acy/Only !edicineV or .(ar#acy !edicineV :V or words of a similar meaning<

A" )oes the label also contain the following informationD a4 the name and strength 2or potency in the case of a biochemical preparation4 of each active ingredientU b4 the dose or directions for use if the product is a physicianQs sample pack or an O#C medicineU c4 PCaution 5 not to be takenQ or P9or eJternal use onlyQ or similar wording if the product is for eJternal useU d4 the name and address of the manufacturer sponsor or distributor 2as applicable4U e4 the batch0lot numberU 0%(e dra t la&el s(ould indicate its place#ent*1 f4 the eJpiry dateU 0%(e dra t la&el s(ould indicate its place#ent*1 g4 the recommended storage conditions if applicableU h4 all warning statements re,uired by 'egulation 22 as applicableU i4 the names and strengths of any antiseptics and0or preservatives if the medicine is for inHection or is a biochemical preparationU C" 6s the product intended for sale without a )rescri)tionU 6f so is all of the following information grouped together on the Consumer 6nformation 8anel 2C684 or if the label is too small on a separate information sheetU the purpose for which the medicine is recommended any warning statements re,uired to appear on the label the recommended storage conditions

%49

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001
a*elling (hec2list for Medicines -cont4d/

(tick &ox)

80 ')ecial Re?uirements
2!edicines 'egs 1N S $mendments S !isuse of )rugs 'egs 2+4

%es No

$" 6s the product a controlled drugU 6f so does the label include all of the following information as re,uired by 'egulation 2+ of the !isuse of )rugs 'egulations 2in addition to the information re,uired by the !edicines 'egulations4U a4 the words FCO7#'OCC@) )'-GG in conspicuous block letters followed by the appropriate designation 2i"e" class code $ A1 C1 etc"4 indicating in which part of which schedule to the !isuse of )rugs $ct the controlled drug is listed b4 the name of the controlled drug c4 recommended dose and fre,uency if for internal use O' directions for use if for eJternal use d4 the name of the preparation miJture or article 2i"e" dose form4 if any e4 the amount of the controlled drug in each dose unit or in the preparation including a statement of whether any percentage strength is calculated on the basis of weight in weight weight in volume or volume in volume A" 6s the product re,uired by 'egulation K* to be in a safety container 2blister pack4U 6f so is each of the following re,uirements of 'egulation K* metU a4 each dose unit container 2i"e" blister4 is labelled withD the trade name of the product the pharmacopoeial name0appropriate designation of the medicine or the name of each active ingredient the strength of the medicine b4 each stri) of containers 2or each container if not in a strip of containers4 is labelled with the manufacturerQs batch number0code c4 the container2s4 or strips of containers is0are enclosed in a package that is fully labelled" C" 6s the product packaged in a safety container 2blister pack4 or a sachet less than K+ mm at its greatest dimension even though not re,uired by 'egulation K* to be in a safety containerU 6f so is each of the following re,uirements metU a4 each stri) of containers is labelled withD the trade name of the product the pharmacopoeial name0appropriate designation of the medicine or the name of each active ingredient the manufacturerQs batch number0code b4 the container2s4 or strip2s4 of containers is0are enclosed in a secondary package 2e"g" carton4 that is fully labelled"

%47

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001
a*elling (hec2list for Medicines -cont4d/

(tick &ox)

')ecial Re?uirements> cont4d


)" 6s the product a transdermal patch and packaged in a pouch or sachetU 6f so is each of the following re,uirements metU a4 each )ouch or sachet is labelled withD the trade name of the product the name and strength of each active ingredient the manufacturerQs batch number0code the eJpiry date b4 the pouch2es4 or blisters4 is0are enclosed in a secondary package 2e"g" carton4 that is fully labelled" c4 the pouch2es4 or blister2s4 is0are not for individual sale apart form the secondary package d4 #he product is not a Controlled )rug

%es No

@" 6s the product sterile and packed in a primary container 2ampoule vial dental cartridge etc"4 that is too small to bear all of the information normally re,uired on a labelU 2;ee ;ection 12 of New Zealand
Regulatory Guidelines or !edicines "olu#e $ for details"4 6f so is each of the following re,uirements of 'egulation 1N and $mendments metU a4 each )rimary container is labelled withD the trade name of the product 2if any4 the pharmacopoeial name0appropriate designation of the medicine or the name of each active ingredient the strength of each active ingredient b4 the )rimary container-s/ is0are enclosed in a package that is fully labelled"

90 6ac2age &nserts> etc0


6s any product information leaflet or any other additional written pictorial or descriptive matter on or attached to or supplied or displayed with the productU 6f so is it consistent with the approved data sheet or 7E5approved details of the productU
(end o or#)

%45

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

A))endi1 1,:

a*elling (hec2list for (ontact ens 'olutions

%46

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

AFE

&NG (7E(H &'# F$R ($N#A(# EN' '$ "#&$N'

6roduct: """""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""?""""""""?"""""""""""
27ame and dose form4

a*el assessed: """"""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""???""""""""""""""""""""""""


2e"g" 8rimary label on container ;econdary label on outer package #ertiary label on outermost package4

(tick &ox)

10 6hysical a*el
6s the labelD

2!edicines 'egs 1*4

%es

a4 printed on or firmly and securely attached to the containerU b4 unlikely to become detached or defaced or illegible during useU c4 positioned so that it will not be damaged or removed when the container is openedU d4 not obscured by any other label or leaflet or any part of the product or packagingU

+0 anguage and #e1t


a4 in @nglishU

2!edicines 'egs 1* and 1&4

6s all the information re,uired to be on the label

b4 in lettering that is clear distinct and legible and the height of letters with ascenders is not less than 0"*+mm in the case of a small label or not less than 1"+mm in any other caseU

30 6rinci)al !is)lay 6anel

2!edicines 'egs 1K S 1+ S $mendments4

)oes the label have a 8rincipal )isplay 8anel 28)84 that is visible when the container is stored in the normal mannerU )oes the 8)8 contain the following informationD a4 the trade name of the productU b4 a description of the preparationU c4 the net contents of the container 2weight volume or number4U d4 the dose form or presentationU

%4"

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001
a*elling (hec2list for (ontact ens 'olutions -cont4d/

(tick &ox)

50 $ther Re?uirements 2!edicines 'egs 1K4


)oes the label also contain the following informationD a4 a description of the composition including the names and strengths of preservatives and any other ingredients critical to the performance of the solutionU b4 full instructions for useU c4 the name and address of the manufacturer sponsor or distributor 2as applicable4U d4 the batch numberU 0%(e dra t la&el s(ould indicate its place#ent*1 e4 the eJpiry dateU 0%(e dra t la&el s(ould indicate its place#ent*1 f4 the types of lens with which the product can be used and if appropriate a statement that the solution should not be used with any particular type of lensU g4 the precautions to take when using the product 2e"g" the words FCautionD 7ot to be #aken or F9or @Jternal -se OnlyG or F7ot for use directly in the eyeG or words of similar meaning as applicable4U h4 a statement about the shelf5life of the opened containerU i4 the properties of the solution such as pB tonicity and bufferingU

%es No

80 6ac2age &nserts> etc0

2!edicines 'egs 2+4

6s any product information leaflet or any other additional written pictorial or descriptive matter on or attached to or supplied or displayed with the productU 6f soD a4 is it consistent with the 7E5approved details of the productU b4 can you confirm that it does not contradict or modify any statement or label re,uired by the 'egulationsU

%92

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

A))endi1 11:

a*elling (hec2list for Related 6roducts

%9!

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

AFE

&NG (7E(H &'# F$R RE A#E! 6R$!"(#'

6roduct: """"""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""
27ame dose form and strength and flavour if applicable4

a*el assessed: """"""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""???""""""""""


2e"g" 8rimary label on container ;econdary label on outer package4

(tick &ox)

10 6hysical a*el
6s the labelD

2!edicines 'egs 1*4

%es

a4 printed on or firmly and securely attached to the containerU b4 unlikely to become detached or defaced or illegible during useU c4 positioned so that it will not be damaged or removed when the container is openedU d4 not obscured by any other label or leaflet or any part of the product or packagingU

+0 anguage and #e1t


a4 in @nglishU

2!edicines 'egs 1* and 1&4

6s all the information re,uired to be on the label

b4 in lettering that is clear distinct and legible and the height of letters with ascenders is not less than 0"*+mm in the case of a small label or not less than 1"+mm in any other caseU

30 6rinci)al !is)lay 6anel

2!edicines 'egs 1+4

)oes the label have a 8rincipal )isplay 8anel 28)84 that is visible when the container is stored in the normal mannerU )oes the 8)8 contain the following informationD a4 the trade name of the productU b4 the pharmacopoeial name0appropriate designation of the related product or the name of each active ingredient and strengthU c4 the contents of the container 2weight volume or number4U d4 PCaution 5 not to be takenQ or P9or eJternal use onlyQ or similar wording if the product is for eJternal use 2other than a toothpaste4U

%9%

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001
a*elling (hec2list for Related 6roducts -cont4d/

(tick &ox)

50 $ther Re?uirements 2!edicines 'egs 1(4


$" )oes the label also contain the following informationD a4 a description that indicates the nature of the product 2e"g" shampoo toothpaste4U b4 directions for use and fre,uency of useU c4 the name and address of the manufacturer sponsor or distributor 2as applicable4U d4 the batch numberU 0%(e dra t la&el s(ould indicate its place#ent*1 e4 the eJpiry date 2if appropriate4U 0%(e dra t la&el s(ould indicate its place#ent*1 f4 all re,uired warning statementsU A" 6s the product packaged in a blister packU 6f so is each of the following re,uirements metU a4 each stri) of *listers is labelled withD the trade name of the product the name and strength of each active ingredient the manufacturerQs batch number0code b4 the strip2s4 of blister is0are enclosed in a package that is fully labelled"

%es No NDA

80 6ac2age &nserts> etc0

2!edicines 'egs 2+4

6s any product information leaflet or any other additional written pictorial or descriptive matter on or attached to or supplied or displayed with the productU 6f so is it consistent with the 7E5approved details of the productU

%9:

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

A))endi1 1+: !ata 'heet !eclaration

%94

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

NEW ZEA AN! !A#A '7EE# !E( ARA#&$N


2$ll parts are to be completed4

6roduct Name: !ose forms and strengths included in this !ata 'heet:

?????????????????????????""?"" ????????????????????????""??"" ????????????????????????""??""

#his declaration relates to:


(tick one)

a new data sheet conse?uential to an NMA for which consent was ga@etted on: 2)ate4????????? a re.ised data sheet conse?uential to a (MN for which consent was granted on: 2)ate4????????? "" a self=assessa*le data sheet u)date $ther: 2please specify4 ????????????????????????????????""??????

& declare that the )roduct descri)ti.e information accurately reflects the )roduct a))ro.edD)ro)osed for distri*ution in New Zealand and the indications and dosages contained in this data sheet are:
(tick one)

identical to those contained in the currently a))ro.ed NZ data sheet for: """"""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""????""""""""""""""""""""" of """"""""""""""""""""?""""""""
28roduct name4 preparation4 2)ate of

not identical to those contained in the currently a))ro.ed NZ data sheet for: """"""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""????""""""""""""""""""""" of """"""""""""""""""""""""""""""
28roduct name4 preparation4 2)ate of

as a))ro.ed with the NMA for which consent was ga@etted on: """""""""""""""""??""""
2)ate4

as a))ro.ed with the (MN for which consent was granted on: """"""""""""""""""??""""
2)ate4

%99

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001
!ata 'heet !eclaration Form -cont4d/

and the safety information in this data sheet is:


(tick one)

the same as the safety information in the )u*lished NZ data sheet for: """"""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""????"""""""""""""""""""" of """"""""""""""""""""?""""""""
28roduct name4 of preparation4 2)ate

the same as the safety information in the currently a))ro.ed: Australian 6rescri*ing &nformation "'6!R document (anadian 6roduct Monogra)h "H !ata 'heet Euro)ean 'ummary of 6roduct (haracteristics (om)any international )rescri*ing information
:$ttach a copy of the source document showing date of approval<

and all re?uired NZ safety information -listed in the NZ Regulatory @uidelines for "edicines Bolume 1/ is included in this data sheet0
Name> designation and address of )erson su*mitting the data sheet:
:$ll correspondence relating to the data sheet will be sent to this person unless re,uested otherwise"<

Email address:

'ignature: ????????"????? !ate: ??????????????"? Name and address of s)onsor:

%97

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

A))endi1 13: (hec2list for NZ Format !ata 'heet

%95

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

(7E(H &'# F$R NEW ZEA AN! F$RMA# !A#A '7EE#


6roduct name""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""?????"""""""""""""""""" !ate of )re)aration of data sheet"""""""""""""""""""""""""""""""""""""????????""" Note:
1" #his check list is to be used only for data sheets prepared using the New Zealand format as detailed in the !edicines 'egulations" 6t is not for use with data sheets based on an overseas approved data sheet" 2" Where only a F>esG boJ is given the heading or information indicated must be included in the data sheet" K" $ny non5compliant aspect of the data sheet should be eJplained in an accompanying letter"

6ndicate whether the data sheet includes each of the followingD

%es
1 2 K ( + N * & % 10 11 12 1K 1( 1+ 1N 1* 1& 1%

NDA

#rade name of the medicine 6harmaco)oeial name or &NN of the medicine or each acti.e )harmaceutical ingredient 'trength of each acti.e )harmaceutical ingredient 8harmacopoeial grade A6resentationB heading )escription of each available dose form including strength colour flavour dimensions and markings A"sesB heading AActionsB su*heading 8harmacotherapeutic group !echanism of action 8harmacodynamic effects Onset and duration of action $ntibiotic class $ntibiotic nature and mode of action 6nformation on the concentration dependent bactericidal activity ;usceptibility data with species listed alphabetically under relevant categories #able of resistance categories Clinically relevant !6C ranges )etail of the in vitro methods e"g" inoculum siLe source of strains

%96

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

%es
20 21 22 2K 2( 2+ 2N 2* 2& 2% K0 K1 K2 KK K( K+ KN K* K& K% (0 (1 (2 (K (( (+

NDA

A6harmaco2ineticsB su*heading $bsorption and bioavailability data )istribution data 5 plasma protein binding volume of distribution tissue and plasma concentration Aiotransformation data for active metabolites inactive metabolites and active substance in the case of a prodrug @limination data 5 elimination half life total clearance eJcretion routes with reference to actives and metabolites 'elationships between plasma0blood concentrations and therapeutic activity or adverse reactions Variations in the pharmacokinetic profile with respect to age concomitant pathological status or polymorphic metabolism A&ndicationsB su*heading 8urpose of the medicine Cist of 7E5approved indications A!osage and AdministrationB heading )ose dosage interval and timing in relation to food )uration of treatment )osages with respect to age category including paediatric )osage adHustments for renal and hepatic insufficiency )osage adHustments for other concomitant disease $dvice for monitoring 8rocedural steps that are critical to the safe administration of the medicine A(ontraindicationsB heading Cist of all situations where the medicine should not be used AWarnings and 6recautionsB heading ;ignificant preclinical results including mutagenicity and carcinogenicity studies ;ignificant warnings for patients with renal hepatic or cardiac failure and any other warnings 2e"g" habituation4 )escription of conditions under which may be recommended to sub5groups of at5risk patients 8recautions to prevent or decrease the harm from adverse reactions Conclusions from animal reproduction0fertility studies

%9"

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

%es
(N (* (& (%

NDA

'isk of use in pregnancy and class statement used in the (th edition of .rescri&ing #edicines in pregnancy )ata on the use of the medicine by fertile or pregnant women 6nformation on the eJcretion of actives or metabolites in breast milk and conse,uences for the well5being of the child One of the following statements 2or words of similar meaning4 plus any relevant warnings or precautionsD 8resumed to be safe or unlikely to produce an effect on the ability to drive or use machinery Cikely to produce minor or moderate adverse effects on the ability to drive or use machinery Cikely to produce severe adverse effects or presumed to be potentially dangerous on the ability to drive or use machinery AAd.erse EffectsB heading $ list of all adverse reactions occurring at a fre,uency of 1M or more 2i"e" significant4 and all serious or potentially serious adverse reactions 9re,uency of each significant adverse effect and an indication of severe or serious adverse reactions" !$'C0!$$C5recommended statements A&nteractionsB heading 6nteractions with other medicines other substances etc" including mechanism of action effect on plasma levels clinical conse,uences and recommendations on dosage adHustment $bnormal laboratory test results associated with the medicine 6nteractions with food or alcohol A$.erdosageB heading ;ymptoms of overdosage #reatment of overdosage A6harmaceutical 6recautionsB heading ;helf life of the medicine as packaged" ;helf life following reconstitution and after first opening 2if appropriate4 6nstructions for dilution or reconstitution !aJimum and0or minimum storage temperatures ;pecial storage precautions with regard to humidity or light

+0 +1

+2 +K +( ++

+N +* +& +% N0 N1 N2 NK N( N+ NN

%72

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

%es
N* N& N% *0 *1 *2 *K *(

NDA

6ncompatibilities with other medicines ;ignificant problems of sorption of the medicine to the container AMedicine (lassificationB heading Classification statement A6ac2age IuantitiesB heading 8ack siLes of each dose form and strength AFurther &nformationB heading 'elevant information that does not fit into any other section such asD chemical structure list of eJcipients provisional consent under section 2K of !edicines $ct and any specific conditions applying to distribution of the product in 7ew Eealand AName and AddressB heading 7ame business address and telephone number of the sponsor company A!ate of 6re)arationB heading )ate

*+ *N ** *&

%7!

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

A))endi1 15: Form for Re)orting 'u))ly of "na))ro.ed Medicine

%7%

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

Medsafe !eclarationDNotification Form for medicines su))lied )ursuant to 'ection +< of the Medicines Act 1<;1
&NN D generic name of medicine: #rade name of medicine: !ose form: Month and year of su))ly: & declare that: the above named medicine was supplied under the provisions of section 2% of the !edicines $ct 1%&1 during the month stated above the name of the medicine as stated above is correct the following records have been keptD

the name2s4 of the medical practitioner2s4 who re,uested the supply of the medicine the name2s4 of the patient2s4 the medicine was re,uired for the dose form2s4 and strength2s4 of the medicine the date2s4 of the month the medicine was supplied the name2s4 of the place2s4 the medicine was supplied to

the complete and accurate records are available for audit by !edsafe the ;upplier has a licence issued under the !edicines $ct 1%&1 which allows the supply of the medicine or is eJempt from this re,uirement under section 2N" 'ignature:"""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""" Name> !esignation> Address and (ontact !etails: !ate:"""""""""""""""""""""""""""""""""""""""""

Name and address of 'u))lier> *eing the New Zealand im)orter or manufacturer:

%7:

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

A))endi1 18: Form for Re)orting Ad.erse Reaction to Medicines> Vaccines> Medical !e.ices and &MM6

%74

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

#or% +or )eporting d&erse )eactions to -edicines9 :accines and 0e&ices and all Clinical 4&ents +or I--P
<!954 PATI>NT 'urname& A Address&

Birst Name s#&

Nat <ealth Inde( No Do1 'e(

A00 M>DICIN>' IN A'> 3 A'T>RI'G 'A'P>CT M>DICIN> '#


Medicine s#F $accine s# U batch no Dail* Dose Route Date 1egun Date 'topped Reason for Ase

D>'CRIPTI=N =B AD$>R'> R>ACTI=N =R INCID>NT


Date of =nset ..............................................................

Reco)ered 'e)ere M

Wes

Not *et reco)ered

No

Rechallenge M

An8nown Batal Date of Death& .......................................... No Wes Result& ................................................................................................


=ther Medical Condition =TCs Industrial+ Agricultural Chemicals etc.

=T<>R BACT=R' 3 Please circle


Renal Disease <epatic Disease Allerg*

R>P=RTING D=CT=R.P<ARMACI'T Name& Address& 'ignature& ....................................................................... Telephone& Date& ............ ............ ............

DANG>R.?ARNING& ................................................................................

Input b*& ......................................................

Date& .......................

%79

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

A))endi1 19: Form for Re)orting Ad.erse Reaction to Fractionated Flood 6roducts

%77

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

#or% +or )eporting d&erse )eactions to #ractionated 2lood Products


8$#6@7#
;urname 9irst 7ame2s4 7at" Bealth 6nd" 7o"

$ddress )iagnosis0main problem2s4 ;urgical 8rocedures 2with dates4

)ate of birth 0 0

;eJ ! 0

ACOO) 8'O)-C#;
Alood 8roduct !anufacturer Aatch 7umber @Jp" )ate )ose0volume )uration of #ransfusion )ate0#ime

8revious $dministration

!@)6C67@; 67 -;@
!edicine 'egular0current medicines 8re5medication $naesthetics0medicines during procedure !edicines after procedure 'oute )ose )ate0#ime started )ate0#ime stopped )uration

)@;C'68#6O7 O9 $)V@';@ '@$C#6O7 O' 67C6)@7#


)ate of onsetD""""""""""""""""""""""""""""" #ime transfusion startedD""""""""""""""" #ime of onsetD""""""""""""""""""""""""""""""

Reco)ered 'e)ere M

Wes

Not *et reco)ered

No

Rechallenge M

An8nown Batal Date of Death& .............................................. No Wes Result& ....................................................................................................

=T<>R BACT=R' 3 Please circle


Renal Disease <epatic Disease Allerg* =ther Medical Condition =TCs Industrial+ Agricultural Chemicals etc.

R>P=RTING D=CT=R.=BBIC>R
Name 'ignature&................................................ Address Date&.................................. Telephone&.......................... Ba(&....................................

%75